Module 9 2021

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

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MODULE 9 - Registration of Biological, Biotech and Advanced Therapy Products

First Name

Last Name

Company

Country

Ofeyemi

Afolabi

Orchard Therapeutics

UK

Mohak

Agarwal

D M Pharma Consulting Ltd

United Kingdom

Salmah

Ahmed

Anthony Nolan

United Kingdom

Resu

Alloza

ReAl CMC Consultancy

Netherlands

Júlia

Aszalós

Gedeon Richter Plc

Hungary

Jayeeta

Bhattacharya

Ethypharm UK

United Kingdom

Sigrid

Booms

Herantis Pharma

Finland

Andrey

Bulimov

Takeda Pharmaceuticals International AG Switzerland

Agathe

Cabarrot

AstraZeneca - Cambridge

United Kingdom

Edmar

Campos

Ipsen Innovation

France

Ingeborg

Cebulla

Boehringer Ingelheim International GmbH Germany

Lisa

Davies

LD Regulatory Consultancy

United Kingdom

Sofie

De keersmaecker

Phara Plus Life Science Services

Belgium

Katharina

Duchardt

Curevac

Germany

Katarzyna

Falentra

AstraZeneca - Cambridge

United Kingdom

Paul

Faulds

Mariscal-Faulds CMC Ltd.

United Kingdom

Alexander

Ferguson

MHRA

United Kingdom

Doerte

Gade

Boehringer Ingelheim International GmbH Germany

Tom

Goldschmidt

Medical Products Agency (MPA) Sweden

Sweden

Eva

Hatzmann

Sanofi

Netherlands

Kieran

Herrity

NHSBT

United Kingdom

Naomi

Krikman

IDEA Regulatory

United Kingdom

Kadi

Kuuskmae-Perry

DLRC Ltd.

United Kingdom

Sephora

Laloupe

PharmaLex UK - Redruth

United Kingdom

Ines

Lenic

AstraZeneca - Cambridge

United Kingdom

Sorina

Luhan

Icon

UK

Ryan

Macbeth

Aspen Pharma Trading Limited

United Kingdom

Leoni

Mahal

Achilles Therapeutics

United Kingdom

Ryan

McCoy

Cell and Gene Therapy Catapult

United Kingdom

Tracey

Miller

NHS

United Kingdom

Helen

Murray

NHS

United Kingdom

Tanja

Novkovic

Boehringer Ingelheim International GmbH Germany

Mai-An

Pham

AstraZeneca - Cambridge

United Kingdom

Isabel

Prieto Gonzalez-Albo

PSIOXUS

United Kingdom

Gwyneth

Rodrigues

United Kingdom

Marian

Roesinger

MaxiaStrategies GmbH

Switzerland

Sabine

Schiemann

Boehringer Ingelheim International

Germany

Jayprit

Serai

GSK

United Kingdom

Liora

Shachar

Israel

Ksenia

Sitara

Oxford Biomedica (UK) Limited

United Kingdom

Roza

Stevens

Allergan Limited

United Kingdom

Imade

ARGENX BV

Belgium

Thiebaut

Estelle

Truchet

Emergent BioSolutions Berna GmbH

Switzerland

Joost

Uitdehaag

Lava Therapeutics B.V.

Netherlands

Andreina

Vallenilla

Grunenthal GmbH

Germany

Fausta

Viola

Sun Pharma Italia Srl

Italy

Giorgia

Volpi

Chiesi Farmaceutici S.p.A

Italy

Neil

Wyborn

Bayer Plc

United Kingdom

Module 9: Registration of Biological, Biotechnology and Advanced Therapy Products 22 - 24 March 2021 Online

Module Leader : Rhydian Howells

Date: Monday 22 nd March 2021

Chair:

Time

Activity

Speaker

09.15 – 09.30

Welcome & Introduction to the Module

Lecture 1: Development of Regulation of Biologicals

Mark Richardson Richardson Associates

09.30 – 10.30

10.30 – 11.00

Refreshment Break

Lecture 2: Module 3 Guideline Requirements

Richard Keane Biogen Idec

11.00 – 12.00

12.00 – 13.00

Lunch

Lecture 3: Clinical Development of Biopharmaceuticals

Tara Hutton Biogen Idec

13.00 – 14.00

14.00 – 14.30

Refreshment Break

Alison Wolfreys UCB Celltech

14.30 – 15.00

Lecture 4: Preclinical Testing of Biologicals

Lecture 5: Viral safety and TSEs

Anne Stokes GlaxoSmithKline

15.00 – 16.00

Version: 7-Mar-19

Module 9: Registration of Biological, Biotechnology and Advanced Therapy Products 22 - 24 March 2021 Online

Date : Tuesday 23 rd March 2021

Chair:

Time

Activity

Speaker

Rhydian Howells

Lecture 6: Implications and Regulations of Changes during Process Development

09.00 – 10.00

Diamond Pharma Services

10.00 – 10.30 Refreshment Break

10.30 – 12.30 Case study

Richard Keane

12.30 – 13.30 Lunch

Cecil Nick Parexel

13.30 – 14.30

Lecture 7: Regulation of Biosimilars

14.30 – 15.00 Refreshment Break

Lecture 8: Immunogenicity issues

Isabelle Cludts NIBSC

15.00 – 16.00

Version: 7-Mar-19

Module 9: Registration of Biological, Biotechnology and Advanced Therapy Products 22 - 24 March 2021 Online

Date: Wednesday 24 th March 2021

Chair:

Time

Activity

Speaker

09.00 – 10.00

Lecture 9: Bioassays

Paula Urquhart

Covance

10:00 – 10.30

Refreshment Break

10.30 – 11.30

Lecture 10: Regulation of Vaccines

Andrew Deavin GSK Vaccines

11:30 – 12.30

Lecture 11: Regulation of Gene and Cell Therapy Products

Sergio Fracchia Novartis

12.30 – 13.30

Lunch

13.30 – 15.15

Case Study 2

Sergio Fracchia (Lead)

Version: 7-Mar-19

Masterclass

Development of Regulation of Biologicals

… and the journey from there to here …

22 March 2021

Mark Richardson PhD FTOPRA

Richardson Associates Regulatory Affairs Ltd Oxford, UK

T: +44 (0)1844 279821 E: mark.richardson@richardsonassociatesra.com

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

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From there to here ...

• Where have we come from?

• Why have we come here?

• What has happened during the journey?

• Who joined us on the way?

• What is it like here?

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Biologicals Old, new, high tech, low tech

• “Traditional” Biological Products – vaccines, serums – allergens, extracted hormones – blood products

• Biotech Products (1 st generation) – r-hormones, vaccines, thrombolytics – r-interferons, cytokines, haematopoietic factors – monoclonal antibodies

• Biotech Products (2 nd generation) – biosimilars

– gene therapy products – nucleic acid products – therapeutic vaccines

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Biological Medicinal Product Definition*

A product, the active substance of which is a biological substance

• Produced by or extracted from a biological source, such as – Micro-organisms, organs and tissues of either plant or animal origin – Cells or fluids (including blood or plasma) of human or animal origin – Biotechnological cell constructs (cell substrates, whether they are recombinant or not, including primary cells) • … and for which a combination of physico-chemical-biological testing and the production process and its control is needed for its characterisation and the determination of its quality.

* Part I of Annex I of Directive 2001/83/EC

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Smallpox vaccine manufacture 1891

• “A red heifer calf about two months old, in good flesh and health, is placed upon a bench in a special operating room and strapped on its side with one hind leg fastened vertically against the back of the bench. The area between the thighs, covering about ten inches square and including the teats, is shaved and washed with soap and water, with hydrogen peroxide solution, and finally with sterilized water and then dried with sterilized absorbent cotton. On the area so prepared, one hundred spots are then scarified, each from a quarter to half an inch square. The blood is washed away with sterilized water, and when the bleeding has entirely ceased virus is rubbed on each spot very thoroughly for some minutes; the calf is then returned to its stall. It is examined on the third and following days, and when the vesicles are seen to be at the proper stage of development, which is usually on the sixth day, the calf is again placed upon the bench and the whole shaved area washed twice with sterilized water and once again with peroxide of hydrogen solution. All macroscopic dirt and crust is removed and every scarification is cleansed as thoroughly as possible; then with a sterilized curette each scarification is scraped and every particle of pulp removed into a sterilized glass dish. The pulp taken is weighed, comminuted, and mixed with a measured amount of chemically pure glycerin*, by being passed between glass rollers on which the glycerin flows. There is thus produced a brown syrupy homogeneous emulsion, which is then drawn by a filter pump into sterilized glass tubes, which when full are sealed in a flame at both ends. Each of these tubes holds about 20 cubic centimeters.”

•

* glycerin acted as a preservative

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Where have we come from?

• A dangerous past, with an uncertain future

• Historical use of biological systems to our individual and collective benefit

• Total absence of oversight or control

• Clinical knowledge advanced faster than the development of prevention or cure

• The scientific method was new

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Two centuries ago

Edward Jenner, 14 May 1796

• Pustular material from cowpox lesion (Sarah Nelms, a milk maid)

• Inoculated 8 year old boy (James Phipps)

• Boy inoculated with smallpox 6 weeks later

• No infection occurred

If Jenner’s clinical trial and investigation product had been constrained by a competent authorities and ethical oversight, would vaccines have started here?

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One century ago

• Further vaccines: rabies (Pasteur, 1885), cholera (1892), typhoid (1898), tuberculosis (1921), pertussis (1923), (mumps (1949), polio (1954), etc .

• Antitoxins: diphtheria (1894), tetanus (1927)

• Blood products: plasma fractions (Cohn), serum albumin for shock WW2, insulin (Banting & Best 1923

• Antibiotics: penicillin (Fleming 1928), started in 1939

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Why have we come here?

Hazards of biologicals

• Ten children die in 1901 St Louis diphtheria epidemic tragedy – Tainted diphtheria antitoxin serum produced from horses – Traced to C.tetani infection in one horse

• 207 children in 1930 Lubeck incident contract TB (72 deaths) – BCG substitution with virulent strain

• 600 children infected in 1948 Kyoto-Shimane tragedy (84 deaths) – Incompletely detoxified diphtheria toxoid

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Hazards of blood products

• 1980s: HIV infected donated blood

• 1991: HAV from Factor VIII

– Solvent detergent treatment inadequate

• In 2,772 male US haemophilia patients – 30% +ve for HBV – 64% +ve for HCV

• 1993/4: HCV from co-fractionated IVIG

• 1994: HBV from pasteurised prothrombin concentrate

• 2001: product withdrawals from donors exposed to tick-borne pathogens

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Hazards of biotech products

• rHu Erythropoietin (various): variations in potency

• rHu Erythropoietin (Eprex): red cell aplasia

• rHu Factor VIII: suspected penicillium contamination

• PEG-rHu MGDF: thrombocytopenia

• Gene therapy: Gelsinger, X-linked SCID trials

• mAb TGN1412 : CD 28 agonist, phase 1 cytokine storm

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What happened on the journey?

Early on, it dawned on us that:

• Manufacturing technology was facile – Extraction with little or no processing – Collection and fractionation – Expansion/culture and modification

• High dependence on facility and raw materials

• Minimal analysis

• Inconsistency/quality attributes not detectable

• Manufacturing errors unchecked

• Biological activity/potency determined utility

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Early in the journey

Consequential conclusions:

• Realisation of attributes of biological products and their variability

• Awareness of serious hazards

• Importance of consistency in manufacture through analysis

• Recognition of need for controls on raw materials, process and facility to reduce risk

• Concept of Quality: using well-controlled ingredients to manufacture a product of consistent standard

• Concept of oversight: the birth of regulation

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Origin of Regulation

Patient safety was and remains paramount

• Regulation is the codified balance between risk, hazard and benefit to the patient • Regulation has evolved as perceptions of risk and hazard have changed • For a biological drug there are safety issues arising from both the product and from its production process

product:

pharmacology

process:

impurities

toxicology

contaminants

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Evolution of regulation

Biologics and drugs become separate product classes

• Final product testing dominated safety assurance for drugs

• Process and facility controls were used to regulate biologics

• Such was the nature of the products and technologies of the day available for their production and analysis

• This was the origin of the dual (establishment and product) licence system for biologics in the US

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Later in the journey

The biotechnology revolution of the ‘70s and ‘80s

• Genetic manipulation and recombinant gene expression • Monoclonal antibody technology • Protein engineering • Enormous advances in analytical and manufacturing technologies

• Commercially viable routes to replace existing products and satisfy unmet clinical needs de novo • Greater safety assurance through product knowledge and process control

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Consequences of advances in technology

New hazards become apparent

• Contaminants in starting materials – With biological/pathogenic activities - viruses – New agents – TSE

• Very difficult to test at low levels due to insensitivity of bioassays – Endogenous viruses – Adventitious agents

• Raw material control becomes critical – Provenance, traceability (geographical origin) – Testing, validation

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Consequences of advances in technology

• Need to demonstrate process capability – Inactivation/removal of viruses – Beyond the likelihood of reaching the patient

• Effects of process inconsistency – Changes in product attributes • Post-translation changes • Impact on potency → efficacy

• Consequences for safety → immunogenicity • Product = process …

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Evolution of Regulation

Realisation of the ‘90s

• Process technology and validation can address safety in manufacture

• Analytical technology approaches the standards for small molecule testing

• Safety of the product can be separated from the safety of its process?

Can biotech products therefore be regulated like synthetic drugs?

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Who joined us on the way?

Regulators • Setting standards and providing oversight • Responsible for: – Assessing purity, potency and safety – (Later: quality, safety and efficacy) – Providing technical guidance – Managing the regulatory approval process – Accountable to their respective populations • Diverse requirements and systems evolved – Individual governments responsible for public health – No prospect of mutual recognition

• Multinational marketplace inaccessible – Retarding effect

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Regulators

• United States

– 1919 National Institutes of Health – 1972 FDA Bureau of Biologics – 1987 FDA CBER – 2001 onwards CDER/CBER

• United Kingdom

– 1925 Therapeutic Substances Act • State testing laboratories • Licensing of premises – 1968 Medicines Act (Medicines Control Agency) – 1975 Biological Standards Act (NIBSC) • Substances whose quality or potency cannot be adequately tested by chemical and physical means – 2003 Medicines and Healthcare products Regulatory Agency – 2013 MHRA and NIBSC merge

• European Union

– 1995 European Medicines Evaluation Agency – 2004 European Medicines Agency

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Harmonisers

Two principle harmonisers

• A coalition of regulators and manufacturers to satisfy each others’ needs and ends – International Council on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (1990) – Tripartite agreements representing consensus between 3 regions – US, EU and Japan (+ observers) – Each contribute authority and industry representatives – Dedicated function • A global organisation supported by governments to provide minimum standards for the world – World Health Organisation – Little industry involvement (mostly philanthropic) – Many other functions

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Later still in the journey

• The concept of comparability is introduced to enable assurance that changes in the manufacturing process can be shown to have no adverse effect on product Q, S & E

• The concept of biosimilarity is introduced to address the commercial imperative of genericisation (analogous to small molecule products)

• The development of high technology products such as gene and cell therapies with their contingent unknown hazards and unquantifiable risks requires significant additional control and regulation in a new category: advanced therapy medicinal products

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What is it like here?

• We are heavily regulated

– This is a good thing, but expensive

• Extensive technical guidance is available

• Guidance is harmonised

• Advice is easily accessible

• We understand established development and regulatory pathways

• Industry and regulators can collaborate

• Regulators are proactive in the face of advancing technology

• Unmet clinical needs can be addressed

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For biologicals in particular

The journey has reached a destination at which:

• Precedent hazards and their risks of occurrence have been characterised – They have been eliminated, or – They can be mitigated

• Known potential hazards can be mitigated

• Harmonised regulatory guidance is in place – Applied on a case by case basis

• Key aspects addressed by guidance – Quality – Safety

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For biologicals in particular • The Q, S & E data requirements for product approval submissions are presented in harmonised regulatory procedural guidance for the Common Technical Document, acceptable now in essentially all regulatory jurisdictions • The ICH CTD guidance describing the core of a MAA or BLA dossier has clearly defined requirements for: – Structure

– Format – Content – Granularity – Relationships between sections

• The expectations of regulatory reviewers must be carefully matched, regardless of product class, and a successful filing is contingent on a clear understanding of how the file is put together

• An awareness of common deficiencies, notably for biological product submissions, is a first step in getting it right

Module 3 Guidelines & Requirements Richard Keene

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For biologicals in particular

• The clinical development of biologicals and its regulation has a variety of product specific aspects which need to be carefully navigated

• Remember that the majority of technical guidance relates to standards required for product approval (this is changing), not for clinical investigation

• It is necessary to summarise clear quality and preclinical safety information for clinical trial regulators in order to address the critical benefit risk evaluation, particularly for FIM studies.

Clinical Development of Biopharmaceuticals Tara Hutton

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For biologicals in particular

• Safety testing of biologicals is inevitably complicated by the common mismatch between test article specificity, selection of test species, dose, route of administration, duration of exposure, immunogenicity and so on • Another perfect example of the case by case basis applies here in a situation where guidance can really only aim to be indicative rather than definitive

Preclinical Testing of Biologicals Alison Wollfreys

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For biologicals in particular

• Control of raw materials for endogenous and adventitious agents and validation of process capability to remove and/or inactivate such contaminants is a key part of biologicals development

• The guidance is now mature and the technology sufficiently well understood to have become routine

• But there complexities and careful evaluations of strategy required

Virus Safety and TSEs Anne Stokes

The Organisation for Professionals in Regulatory Affairs

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For biologicals in particular

• The concept of product comparability is now established and supported by comprehensive technical guidance

• Even so, the case by case basis approach must be taken in evaluating process change, consequences for the product and the subsequent demonstration of new product comparability with old • The infinite variety of comparability scenarios cannot be covered by an infinite repertoire of guidance, so cerebral interpretation is required

The Organisation for Professionals in Regulatory Affairs Implications and Regulation of Changes During Process Development Rhydian Howells

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For biologicals in particular

• The relatively new concept of biosimilar biotechnology derived medicinal products has already been realised in the EU

• This has been a tour de force of collaboration between the CHMP and industry and places Europe far ahead in global achievement

• Founded in part on the principles comparability, the discipline has been enabled by proactive regulation

Regulation of Biosimilars Cecil Nick

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For biologicals in particular

• With the exception of vaccines, the immunogenicity of a biological product is potentially an undesirable attribute

• It must be fully characterised and its consequences evaluated in the context of its potential or actual impact on both product potency and safety in preclinical and clinical studies • Subtle changes in product quality can have far reaching immunological effects which might (and in some cases have) radically alter the benefit/risk balance adversely

Immunogenicity Issues Isabelle Cludts

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For biologicals in particular

• The science and technology of bioassays continues to play a central role in defining product quality and safety

• The principal challenge is the linkage of a quantitative measure of biological activity to the medicinal product function and its potency • It is a speciality within analytical science to which the same principles of design, standardisation, qualification, validation and appropriate use are applied

• Bioassays are also complex, challenging, variable (in the nature of biological systems), and absolutely required

Bioassays Paula Urquhart

The Organisation for Professionals in Regulatory Affairs

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For biologicals in particular

• Vaccine technology is now largely unrecognisable compared to its 18 th century antecedents, although the underlying mechanisms are no different

• This has been the longest journey of any product class, and probably the most important one for global public health

• Regulation of product quality, safety and efficacy is required to take into account the need for rapid availability against an emerging infectious agent strain and for population vaccination programmes

Regulation of Vaccines Andrew Deavin

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For biologicals in particular

• The relatively new concept of advanced therapy medicinal products (ATMPs) is now a reality

• The principles apply globally but the EU has erected a dedicated supporting regulatory framework

• The unknown hazard/unquantified risk position is uncomfortable for any emerging technology, consequently the precautionary principle is prominent and risk-based safety evaluation is preferred

Regulation of Gene and Cell Therapy Sergio Fracchio

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And now we are here…

• Thank you for your attention

• Enjoy the Masterclass

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16/03/2021

Richard Keane Global Regulatory CMC Biogen Idec Ltd

The Organisation for Professionals in Regulatory Affairs

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Learning Outcomes

 Understand at a high level the regulations that apply to CTD Module 3 at the time of licensing for these modalities ● Seek to achieve this through generally focussing on the EU and with a direct focus on Module 3 ● Present practical examples where these are helpful

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16/03/2021

Presentation Structure

• Why is Module 3 important? • Evolution of Module 3 alongside product development • Module 3 Differences Inherent in Biologics • Module 3 Level of Detail

• General Structure of Module 3 • Specific Module 3 Components • Practical Considerations • Conclusions

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Why is Module 3 important?

• The philosophy of Module 3 is different to that of Modules 4 & 5 – specifically Module 3 represents a combination of the CMC development + future manufacturing agreements & compliance

• Getting an appropriate Module 3 approved can save companies considerable time, resources, complexity and ultimately money – particularly with global products

• The EU currently considers your entire Module 3 as effectively Established Conditions (ICH Q12)

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Why is Module 3 important (cont.)?

• Module 3 applies equally through IMPD development up to licencing and beyond

• Getting Module 3 into a suitable state is not simply a case of “dumping all CMC information into a defined format”

• Your Module 3 must coherently tell the story of the development while ensuring that continued compliance of your CMC elements are well defined

• Getting Module 3 approved is a requirement for your CTA/MAA but; ● Getting an appropriate Module 3 approved is also critical to lifecycle maintenance and future compliance

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Evolution of Module 3 alongside product development

• Your Module 3 content should evolve and build as your product is developed

• Phase specific expectations are defined in EU IMPD guidance (e.g. biologics, impurities etc..)

• Ideally Module 3 of your MAA should be built from the last IMPD

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16/03/2021

Module 3 Differences Inherent in Biologics

• While Module 3 is defined in the same general way in ICH M4Q, EU NtA etc a Module 3 for a Biologic will be different to a Module 3 for a Small Molecule product

• Typically Biologic focus is much more on 3.2.S (vs 3.2.P. for most Small Molecules)

• Often reflected in separate guidances (e.g. EU IMPD guidance)

• ATMP products are also quite different and guidance is continuing to evolve around these but as more such products get approved the agency expectations will become clearer.

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Module 3 Differences Inherent in Biologics (cont.)

• These differences for Biologics stem from inherent and reasonable concerns around: ● Process variability – what is the potential impact of a small variable?

● Biological Assays – you cannot feasibly fully characterise a biologic using current analytical methodology (what could this potentially hide?)

● Biological contaminants – TSE, viruses etc

● Biological target – how far can nonclinical models simulate human biology?

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16/03/2021

Module 3 Level of Detail

• The level of detail registered in your Module 3 is critical • There is no “one size fits all” model • The ideal scenario would be to register the minimal amount of information while providing sufficient information for regulators • This needs to be balanced with clearly defined requirements in legislation, guidance and current regulatory expectations • There is also a balance to be struck between regulatory and Good Manufacturing Practice requirements in Module 3 (e.g. shipping or hold times) • Currently can be very difficult to maintain a consistent level of detail globally at the IMPD stage (e.g. EU National CTA Assessments) • In time it is hoped that EU CTR and ICH Q12 once fully implemented may help

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General Structure of Module 3

• First point of reference for an EU MAA should be Notice to Applicants Volume 2B, CTD – Module 3 and increasingly EMA pre-/post- authorisation guidance and Q&A • Provides guidance on the format required for a registration application • Provides specific guidance for biologics and small molecules • For the EU also consider: ● Ph. Eur. – has a legal basis ● Scientific guidelines - while not legal requirements deviation from these must typically be strongly justified ● Q&As – driving new requirements

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General Structure of Module 3 (cont.) • Module 3 is essentially broken down into key areas 1. Description of the substance/product 2. Manufacturing Process

3. Characterisation of the substance/product 4. Controls to test the final substance/product 5. Reference material/standards 6. Container closure 7. Stability • Essentially the same for drug substance (3.2.S) and drug product (3.2.P) • Small molecules: option to refer to a Drug Master File/Active Substance Master File in place of or supporting 3.2.S (EU) – DMFs can be a viable option for other elements in other countries (e.g. US, China etc)

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Specific Module 3 Components

• Will not go through all Module 3 components • Focus on key Module 3 sections for Active Substances & Products ● Placebos, NIMPs, comparators are similar but different • Much of the basic content is defined for commercial products in ICH M4Q and for clinical products through regional guidance • Medical Devices continues to be a hot topic which is developing alongside implementation of the EU Medical Device regulation

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Specific Module 3 Components (cont.)

3.2.S.2.2 Manufacturing Process ● Key compliance section ● Describe the manufacturing process (including potential re-processing) with a clear flow diagram ● Typically include limits for critical steps and parameters only ● SM – start with the starting material but typically a simple chemical scheme ● Biotech – start with a vial of the cell bank and a much more detailed description is required as likely to include purification and modification reactions

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Specific Module 3 Components (cont.)

3.2.S.2.3 Control of Materials ● SM –typically straightforward description of the quality of raw materials, solvents, reagents & catalysts ● Biotech – considerably more complex descriptions including control of source and starting materials of biological origin, source history and generation of the cell substrate, cell banking system characterisation and testing

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Specific Module 3 Components (cont.)

3.2.S.2.5 Process Validation ● SM – typically not applicable

● Biotech – considerably more complex section which evolves as a program develops. Essentially you need to provide sufficient information to demonstrate appropriate validation and evaluation of the manufacturing process for the stage of development of your product

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Specific Module 3 Components (cont.)

3.2.S.2.6 Manufacturing Process Development – Critical section for justifying applicability of your current/future manufacturing process to what was used in previous clinical studies – SM – typically not extensive – Biotech – considerably more complex section which needs to clearly assess the impact of each manufacturing change through product development on the drug substance and drug product which can include specific nonclinical or clinical studies

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Specific Module 3 Components (cont.)

3.2.A Appendices ● Largely consistent structure across major ICH regions as well defined in ICH M4Q – 3.2.A.1 Facilities and Equipment – 3.2.A.2 Adventitious Agents Safety Evaluation – 3.2.A.3 Excipients ● Differences in focus (i.e. biologics inherently present a higher adventitious agents risk) ● Differences in maintenance between regions (3.2.A.1 in particular)

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Specific Module 3 Components (cont.)

Module 3.2.R ● Content defined by region in ICH M4Q for US and EU (see screenshot below) (NB - ICH M4Q (R1) pre-dates EU PACMPs = Comparability Protocols)

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Specific Module 3 Components (cont.)

Module 3.2.R (cont.) ● Content evolving in other regions globally – Some have no specific requirements – Some manage regional requirements in Module 1 – Some adopt partial EU or US requirements or their own specific requirements

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Practical Considerations

• Too often Module 3 finalisation is rushed and becomes inconsistent • Ensure that Regulatory schedules time in the review prior to filing to read through the entire Module 3 end to end • Try to ensure that data is not repeated in multiple sections wherever possible • This impacts not only the quality of the Module 3 but can have significant lifecycle repercussions ● Could be as simple as “what can we consider registered for this parameter when it is stated in a different way in Module 3.2.X & 3.2.Y?” • The power of flexible wording such as “typically”/“or equivalent”/”or validated equivalent”

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Practical Considerations (cont.)

• Beyond ICH countries managing post-approval changes gets considerably more complex and costly • Many companies tailor the Module 3 to local markets, redact Module 3 and/or clearly define which details will be maintained • Without that consideration even simple post-approval changes can take 3-5 years to secure global approval • ICH Q12 is seeking to solve some of this but the benefits of this will take time to be evident both within and outside of ICH countries

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Conclusions

• Getting Module 3 correct is important ● Includes location and level of detail

• The data presented in Module 3 must allow the regulators to assess alongside nonclinical and clinical data that the product proposed is suitable for the stage of clinical study (CTAs) or for commercial approval (MAA/NDA/BLA etc) • Inadequate or insufficient CMC information may lead to non- approval • Conversely too much CMC detail may lead to additional questions or significant lifecycle burden

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?? QUESTIONS ??

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Masterclass

Clinical Development of Biopharmaceuticals

22 March 2021

Tara Hutton, Director, Biogen Idec Ltd

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

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Learning Outcomes

 Understand aspects of clinical development for biopharmaceuticals;  Identify key considerations when designing a first-in- human study;  Be aware of the clinical pharmacology of biopharmaceuticals;  Appreciate the continuum of clinical development post first-in-human studies;  Recognise the continuation of clinical development post-approval;

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General Principles

Clinical development of biopharmaceuticals still have the same requirements as other types of investigational medicinal products (IMPs) ● Development of a Target Product Profile (TPP) will drive the clinical development programme (CDP); – Design of the clinical studies that need to be conducted to obtain data to support the TPP ● Pre-MAA activities such as CTAs, DSURs, PIPs, ODD, Scientific advice, PRIME, accelerated assessment are all applicable, where relevant; ● Efficacy, safety and a favourable risk/benefit profile needs to be demonstrated; – Supported by preclinical studies, clinical trials (First-in-human/Phase 1, Phase 2 [Proof of Concept; POC] and Phase 3), post-approval studies, real-world evidence (RWE), risk management plan (RMP)

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Clinical Trials

Governed by the Clinical Trials Directive 2001/20/EC ● Provides guidance on the conduct of clinical trials, highlighting the importance of Good Clinical Practice (GCP) Assessment is conducted at a National Level until the Clinical Trial Regulation (EU 536/2014) becomes effective which will result in a harmonised approach ● Voluntary harmonisation procedure (VHP) was concluded as of January 2021 Clinical Trials Facilitation Group (CTFG) coordinate the implementation of the directive across the member states No distinction in CTA conduct and assessment with different IMP types (Biologic versus small molecule versus ATMP)

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Drug Development and Model Building Learning and confirming

Continuum of learn/confirm/predict at each decision point

M&S

M&S

M&S

M&S

M&S

Preclinical

Phase 1

Phase 3

Phase 4

Phase 2b

Registration Labelling

Phase 2a

FIH

POC Confirmatory

Therapeutic Index

Results relative to competitors, regional differences, therapeutic index

Efficacy

Toleration

Efficacy and safety

Toxicology

Human PK & PD

Dose/exposure-response

Covariate effects

PK-PD

Dose adjustments

Confidence in drug and disease

Uncertainty

M&S: Modelling and simulation; FIH: First-in-human; POC: Proof of concept; PK: Pharmacokinetics; PD: Pharmacodynamics

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Adapted from Lalonde RL et al. (2007) Clin.Pharmacol.Ther. 82:21-32

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Clinical Development

Constantly seeking ways to improve the efficiency of clinical development of IMPs ● Adaptive Trial Designs of Phase 1-2 studies – Initial safety/tolerability, proof-of-concept (POC), dose finding – Where feasible, investigate as many PD parameters as possible – Continually assessing the uncertainty – Ability to modify depending upon the outcome of the assessment of uncertainty ● Modelling and simulation – Based upon PK and PD results – Informs on the IMP throughout clinical development to progress to the next phase – Used to optimise the dose and dosing regimen – Assists to design more efficient POC

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First-In-Human Studies

Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products (CHMP; 2017*) ● Covers all chemical and biological IMPs, excludes advanced therapy medicinal products (ATMPs) ● Highlights the responsibility of the Sponsor to evaluate any associated risks and develop mitigation plans ● A step wise approach to reducing the uncertainty of an IMP by gathering knowledge via well designed studies ● Outlines the importance of relevant preclinical studies to reduce the level of uncertainty for FIH studies

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* EMEA/CHMP/SWP/28367/07 Rev.1

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Considerations Before Preclinical and Clinical Studies

Before studies are initiated, certain considerations need to be made ● Mechanism of Action (MOA) – Is there precedent of products with this MOA (i.e. established experience) or is this a completely new MOA? – Are the effects likely to be reversible or irreversible? – Are there likely to be effects on- or off-target, downstream? – The potential PK/PD profile and could this be impacted by the patients health status? – Is there a suitable animal species to conduct the preclinical studies? ● Immunogenicity – Is there the potential for anti-drug antibodies (ADAs) following administration of the product? – If an antibody response is expected, will this impact the PK/PD or safety profile of the product? – Could an antibody response be monitored or reduced in patients?

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Species Selection ● Relevant species need to express the desired epitope and have similar tissue-cross reactivity profile as human tissues ● Transgenic animals and homologous proteins Activity ● In vitro assays can assist to evaluate effects related to clinical activity, can be useful to predict in vivo activity, in particular sensitivity to the product Pharmacokinetics(PK)/Pharmacodynamics (PD) ● Determination of the no observed adverse event level (NOAEL) Safety Pharmacology/Toxicology/Immunogenicity ● Any target organ toxicity that may require monitoring in the clinical trial ● Formation of anti-drug antibodies (ADAs) and correlation with pharmacological/toxicological changes First-in-Human Studies -Preclinical Considerations ICH S6 (R1) – preclinical safety evaluation of biotechnology-derived pharmaceuticals ICH M3 (R2) – nonclinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals 9

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PK/PD Modelling

E max

C max

AUC

EC 50

E 0

T max

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Estimation of Starting Dose in Man

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Muller PY et al. (2009) Current Opinion in Biotech. 20:722-729

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Maximum recommended starting dose (MRSD)

High risk features observed

No high risk features observed

Toxicological Assessment HED@NOAEL

Pharmacological Assessment MABEL

Step 1: Determine NOAEL in all toxicology species Step 2: Convert NOAEL to HED* for all toxicology species Step 3: Select HED* for most sensitive toxicology species Step 4: Apply ≥10-fold safety factor

Step 5: (a) Estimate human MABEL based on:

(i) In vitro pharmacology studies with target cells from humans and toxicology species (ii) Concentration-effect data from in vitro and in vivo studies (b) Integrate data into PK/PD model, if feasible, in order to predict pharmacological response in humans at multiple dose levels (c) Account for: (i) Animal-human differences in affinity /potency (ii) Animal/human differences in exposure/distribution (iii) Anticipated duration of effect(s)

Maximum recommended safe starting dose (MRSD)

Define anticipated safety window based on NOAEL and MABEL and apply additional safety factor**, if necessary, based on

(1) Potential risk/hazard and uncertainty thereof (2) Degree of uncertainty in MABEL calculation

* Based on body surface area (BSA) scaling; ** A safety factor might also be added to the MABEL dose depending on several factors including risk/hazard and uncertainty thereof.

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Muller PY et al. (2009) Current Opinion in Biotech. 20:722-729

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First-In-Human Studies – Risk Mitigation

Factors to be considered in ascertaining the balance between the degree of uncertainty and potential risks ● Study population ● Trial site(s) ● Number of subjects per cohort ● Sequence and interval between dosing of subjects in each cohort

● Transition to the next cohort/part of study ● Stopping rules/monitoring of adverse events ● Route and rate of dosing ● Dose escalation

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First-In-Human Study Population

Studies in Healthy Volunteers requires justification ● Objective of FIH studies is more focused on assessing safety and tolerability than efficacy ● IMP target may respond differently in healthy subjects compared to patients with the disease of interest – PK can be impacted – Dose-response may be different – Immune status needs to be considered – Safety can be underestimated

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