Michael Whitaker

Advanced Therapy Treatment Centres

The barriers for ATMP delivery and adoption Regulatory Manufacture Early stage trials Late stage trials Adoption

• Cautious hospital research committees

• Clinical trial sites lack of ability to handle live products

• Limited ability to scale-up effective, robust and reliable manufacturing

• Lack of meaningful assays

• Poorly understood health economics

• Entry into NHS slow

2012 - 2017

• Regulatory patchwork • Complex lifecycle requirements

• Licensure for distributed manufacturing model

• BREXIT

• More mature processes but development required

• Scale up /Scale out challenging

• Shortage of trained staff (manufacturing, QA & QC)

• Complex logistics - supply chains poorly developed

• Clinical trial sites lack of ability to handle live products

• Trials are still slow to start

• Patient recruitment is difficult

• Manufacturing and analytics still developing

• Clinical sites require support

• Shortage of trained staff

• Approvals accelerating

• Clinical adoption and reimbursement methodology lagging

2018 - 2023

Complex Value Chain

• Uncertain and complex regulation

• Number of regulatory agencies; T&C, Manufacture, Clinical trial, Licensure

• Non-optimised manufacture - small scale, low efficiency, high COG

• Specialist developers • Facility availability

Immune-oncology Landscape

Immune-oncology Landscape

Gene Therapy Landscape

Gene Therapy Landscape

The challenge

2018 Mainly clinical trial ~200 subjects pa

2021

2028

Licensed products for larger patient numbers 2019

Increased patient delivery ~2500 patients pa

Embedded patient delivery ~10000 patients pa

2023 Routine patient delivery ~5000 patients pa

Route to improved clinical adoption

2018 Mainly clinical trial ~200 subjects pa

2021

2028

Licensed products for larger patient numbers 2019

Increased patient delivery ~2500 patients pa

Embedded patient delivery ~10000 patients pa

2023 Routine patient delivery ~5000 patients pa

ATTC & other specialist centres Accelerated Access Pathway/EAMS

Widespread adoption

Standardised methodology & training programmes established.

Systems embedded in NHS for delivery & reimbursement

Reimbursement mechanisms established for licensed products. Rollout to other centres

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Centraladministrationsite

Suppliers

Data Central Analytics

Logistics

Manufacturers

Clinical Sites T&C procurement Patient management Trial management Experienced Clinical team Pharmacy Distributed manufacturing

Data Service Development Scheduling - Procurement, product, treatment Tracking & Tracing Data and information collection Database & Registry development

Analytical Service Development Central lab function

Distributed lab function Companion Diagnostics

T&C Procurement Treatment

T&C Procurement

Supply Chain Development Interface with data service Patient sample repositories

ATTC – a network

£ mechanisms All territories Exemplar models

An overview of the Centres

iMATCH

From the Industrial Strategy Fund each centre has been awarded ~£7M from 1st March 2018 – 31st March 2021

Northern Alliance Advanced Therapy Treatment Centre objectives : Development of the clinical delivery pathway & use of informatics to achieve utility at scale in clinical pathway

Midlands & Wales Advanced Therapy Treatment Centre objectives: End to end supply chain logistics, network of ATMP capable hospitals, infrastructure for trial roll out, validation with real world manufacturing and trials, economic model for ATMP use

Manchester Advanced Therapy Centre Hub objectives: co-ordination of patient cell collection, processing & storage, track & trace solutions and education through MRes platform

Midlands & Wales Advanced Therapy Treatment Centre

Innovate Manchester Advanced Therapies Centre Hub

Manchester12partners

1city

A coordinated strategy to scale-up advanced therapies for patients in ManchesteriMATCH

Midlands & Wales Advanced Therapies Treatment Centre

Academia NHSProviders

Supporting Industries ATMPSuppliers

Strategic objectives

•  EstablishbestpracticefornearpatientGMP•  Establishrobustconnectedsupplychains•  Establishbestpracticeforsafeandeffectivedeliverytopatients•  Establishbestpracticeforpatientfollowupanddatacapture•  Layfoundationsfortraceabilityandtrackingsystems• DisseminationthroughoutNHS(ScotlandandEngland)includingToolboxesonNAATTCwebsite

•  Increasepatientaccessonaregionalandnationallevel

AT Autologous Supply Chain - Exquisite Integration Required

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 ….

Time

TrakCel Autolus Fisher BS

Miltenyi

IndustrialPartners

CellMovement

Logistics Treatment Centre

Treatment Centre Logistics Manufacture

Centre Apheresis

Centre Cryo

Manufacturing

Supply Chain

WP3

WP4 Infrastructure for clinical trials, reimbursement and adoption

WP5 Wider Network Engagement

WP6 Informatics

Patient – centred delivery

WP2

WP1

WorkPackages

Supply Chain Supply Chain

Preparation

TrakCel

Cell Therapy Challenges “The major challenge in manufacturing this product is not in the manufacturing protocol… Logistics is perhaps the more challenging aspect of producing this product due to the short shelf life of both the incoming apheresis units and the final product. Given the tight manufacturing schedule, short process time limitations, overlapping production schedules, QC testing, and complex shipping situations. It will be difficult to generate this product at high throughput without substantial attention paid to coordinating and orchestrating these events.”

FDA Provenge CMC Review

Because tisagenlecleucel is an autologous product, each lot is produced for a single patient. For this reason, the applicant has implemented strictly controlled tracking and segregation procedures, from apheresis to infusion, to ensure proper chain of identity so that the patient receives the tisagenlecleucel product made from his or her own cells.

FDA Briefing Document of Novartis’ Tisagenlecleucel (Kymriah)

High-Level Process

Definitions Unit of activity Decision point Co-dependent Process Step

Process Steps

Location Collection Logistics Manufacturing Treatment

Process Steps

27 22 76 26

Decisions Steps

8 4 37 5

Each unit of activity characterised for the supply of a CAR-T Therapy

A total of 151 high-level process steps were identified

Almost half of all process steps were related to manufacturing activities

A further 54 decision points were identified

Almost 70% of decision points were associated with manufacturing

Co-dependent decision points

Location Collection Logistics Manufacturing Treatment

Collection x 1 1 1

Logistics 5 x 7 4

Manufacturing 6 9 x 11

Treatment 0 5 9 x

A total of 59 co-dependent decision points were identified for one batch manufacturing exercise

All processing centres have co-dependencies with all other processing centres

Almost half co-dependencies occur during manufacturing

Treatment and logistics steps also need a significant degree of cooperation for safe completion of a treatment cycle

There is significant co-dependence between manufacturing and treatment groups

Michael Whitaker

Advanced Therapy Treatment Centres