Immune effector cells and JACIE accreditation

Professor John Snowden

Sheffield Teaching Hospitals NHS Foundation Trust & University of Sheffield

Chair, EBMT/JACIE Committee

4th French International Symposium on CAR T Cells ‘CAR T day’

Lille 15 January 2020

Haematopoietic Cellular Therapy (HCT)is COMPLEX…

.....and TOXIC......

Low Risk

e.g. autologous transplantation

TRM 1-2%

… with RISKS..

High Risk

e.g. VUD, cord, haploidentical

TRM 10-30%

•

Blood

Brain Pericyte

EndotheliumEndothelial activation

Altered blood–brain barrier

Increased vascular permeability

Inflammatory cytokine release

Macrophage mediator release

Bone

Leukaemia IL-6

CAR T cell

IFN

CAR T-cell therapy is associated with cytokine release syndrome and neurotoxicity

Figure adapted from June CH et al. 20181

ORGAN DYSFUNCTION• Hypoxia• AST and ALT elevation• Acute renal injury• Respiratory failure• Liver failure• Renal failure

HEMODYNAMIC INSTABILITY• Tachycardia• Hypotension• Arrythmia• Capillary leak syndrome• Coagulapathy• HLH/MAS

NEUROLOGICAL EVENTS• Headache• Confusion• Hallucinations• Delirium• Aphasia• Paresis• Seizures• Cerebral oedema• Intracranial haemorrhage

Donation/leukapheresis is not without risks• 5 donor fatalities

• 37 severe adverse events

• 20 hematologic malignancies

International ‘trafficking’ of HCT products

• “there are now around 33 stem cell products being transported every day across the world to facilitate transplants in another country”

• 12,000+ HSCT products exchanged across borders every year

• APPLIES TO CAR T CELLS7

Hwang, W. Y. K., & Foeken, L. M. (2014). Blood stem cell donation: A model for worldwide cooperation in transplantation. Annals of the Academy of Medicine Singapore, 43(6), 294–295.

ATMP cell therapy regulation even more complicated than for HSCT

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Directive 2003/94/EC principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use

REGULATION!

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JACIE has been the response by the EBMT community to allthese ongoing challenges in HSCT and now in the new cellulartherapies…

WHAT IS JACIE?• International standards setting and accreditation organisation allied to

EBMT and ISCT

• Independent of the regulators - established by the practitionersthemselves

• Inspectors are experienced professionals and volunteers

• Closely aligned with FACT

• Compatible with EU and other regulations

FACT-JACIE StandardsPart

A• Definitions

PartB

• Clinical

PartCM

• BoneMarrowCollection

PartC

• Apheresis

PartD

• Processing

533 pages!

PRINCIPLES

Principle 1

•Standards, focussed on Quality Management

Principle 2

•External inspection/Accreditation/Certification

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United

Kingdom

Iceland

Ireland

France

SpainPortugal

Norway

Sweden

Finland

Germany

Greece

Italy

Poland

Russia

Turkey

Ukraine

Denmark

Netherlands

Belgium

SwitzerlandAustria

Estonia

Latvia

Lithuania

Belarus

Czech Rep.Slovakia

Slovenia

Hungary

Moldova

Romania

Bulgaria

Croatia

Greenland

Luxembourg

Lichtenstein

Malta

Andorra

Faroe Islands

2000

2003

2004

2004

2004

2004

2005

20062006

2007

2009

2010

2012

2013

2013

2011

2015

2016

Saudi Arabia 2008

Israel 2009

Singapore 2012South Africa 2012

Lebanon 2015

2018

Year of first applicationby country

JACIE’s journey

1998Voluntary initiativeby the transplant

professionals

Mid-2000+Widespread acceptance

among the BMT profession

NowExternal

recognition e.g.Regulations, Payors,

Validation, CELLULAR THERAPY

FACT-JACIE Standards(7th Ed) apply to:

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1. Hematopoietic progenitor cells from hematopoietic sources (e.g. PBSC, BM)

2. Nucleated cells from any hematopoietic tissue source collected for therapeutic use other than as hematopoietic progenitor cells (e.g. DLI)

3. Immune effector cells (IECs) derived from these sources, defined broadly as anycells, in vitro modified or not, that are capable of eliciting or modulating an immune response.

• This broad designation includes cellular therapy products with widely diverse manufacturing methods, constructs, clinical indications, and safety and toxicity profiles (e.g. CAR T)

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Requirements for IECs including CAR TRegulatory

EBMT, FACTHTA

Government

Manufacturer Requirements

Personnel

Clinical facilities and support departments

Collection, Processing and Pharmacy

Manufacturer

CAR T delivery involves HCPs across a range of departments and requires coordination with the manufacturer

• Regular CAR T-cell meetings

• Ongoing training

• Development of SOPs: • Patient identification

• Apheresis

• Infusion

• Patient monitoring after infusion

• Coordination with THIRD PARTY

Nurses

ANP/PDN

ICU physician Apheresis/ cell

laboratory

MDT coordinator/ administrator

Neurologists

CAR T-cell CNS

Pharmacists

Psychologists

CAR T-cell fellows

Disease-specific and cell-/transplant-experienced

consultants

STANDARDS FOR IMMUNE EFFECTOR CELLS (IECs)

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• Recognise dependency on the wider accreditation requirements of the HCT programme i.e. clinical, apheresis, pharmacy and processing laboratory service, along with quality management system requirements

• Standards do not cover manufacturing , but cover the chain of responsibilities where the IEC product is provided by a third party and ensure competence of the personnel in the management of adverse events related to the infusion

STANDARDS FOR IMMUNE EFFECTOR CELLS (IECs)

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Standards detail the following requirements to protect patients:

• the need for the appropriate recognition of IEC infusion-related side effects

• a policy for the rapid escalation of care in critically ill patients

• the availability of specific drugs for CRS and other complications

• labelling system to guarantee both the identification and traceability of the product from the collection to the manufacturer and back to the clinical unit

• In all involved areas, there is the need for evidence of adequate staffing and training, satisfactory levels of competency, validated procedures and efficient communication.

FACT-JACIE Standards for IECs/CAR TB7.11 There shall be policies or Standard Operating Procedures addressing the administration of immune effector cellsand management of complications, if applicable.

B7.11.1 There shall be a consultation with the referring physician prior to initiation of immune effector cellulartherapy to review the goal and plan of the treatment.

B7.11.2 There shall be regular assessment of the recipient to detect complications, including cytokine release syndrome and neurologic dysfunction.

B7.11.3 There shall be a written plan for rapid escalation of care, increased intensity of monitoring, and relevantworkup to address complications.

B7.11.4 Communication to the clinical staff, intensive care unit, emergency department, and pharmacy shall be timely.

B7.11.5 The Clinical Program shall have written guidelines for management of complications, including the use of cytokine blocking agents and corticosteroid administration.

FACT-JACIE Standards for IECs/CAR TB7.11 There shall be policies or Standard Operating Procedures addressing the administration of immune effector cells and management of complications, if applicable.

B7.11.1 There shall be a consultation with the referring physician prior to initiation of immune effectorcellular therapy to review the goal and plan of the treatment.

B7.11.2 There shall be regular assessment of the recipient to detect complications, including cytokinerelease syndrome and neurologic dysfunction.

B7.11.3 There shall be a written plan for rapid escalation of care, increased intensity of monitoring, and relevant workup to address complications.

B7.11.4 Communication to the clinical staff, intensive care unit, emergency department, and pharmacy shallbe timely.

B7.11.5 The Clinical Program shall have written guidelines for management of complications, including the use of cytokine blocking agents and corticosteroid administration.

+ many other specific and/or relevant standards throughout 7th edition (in sections B, C & D)

IECs Standards: Chain of Responsibilities

• B1.2.1 If the Clinical Program or an intermediary facility receives cellular therapy products directly from a third-party provider, the following responsibilities shall be defined, at a minimum, by a written agreement:

• B1.2.1.1 Traceability and chain of custody of cellular therapy products.

• B1.2.1.2 Cellular therapy product storage and distribution.

• B1.2.1.3 Verification of cellular therapy product identity.

• B1.2.1.4 Review and verification of product specifications provided by the manufacturer, if applicable

• B1.2.1.5 Readily available access to a summary of documents used to determine allogeneic donor eligibility.

• B1.2.1.6 Documented evidence of allogeneic donor eligibility screening and testing in accordance with applicable laws and regulations.

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Inspection of Involved Services (and associated Quality Management Systems)

In all the involved areas, evidence of adequatepersonnel training, workforce, validatedprocedures/SOPs, product identificationand traceability, efficientcommunication……

shall be in place

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Service Action

Outpatient Patient selection

Inpatient/Outpatient Unit Clinical administration, Monitoringand Supportive Care

Apheresis unit Collection, Product quality

Pharmacy Policies, SLAs, Drug availability

ICU Plan for rapid care escalation

Neurology Monitoring and Therapy

Processing lab Storage and thawing

Data Management Outcomes, FU and Registry Report

Standards: Pharmacy policies and procedures

25http://victoryoncology.com/wp-content/uploads/2015/11/pharmo.jpg

Standards: Nursing policies

• B3.7.4 There shall be written policies for all relevant nursing procedures…...

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IECs: TRAINING & COMPETENCY

• Not just transplant physicians and associatedmedical specialists…….but also…...

• B3.7.3 Nurses shall have received specific training and maintaincompetence in the transplant-related skills that they routinelypractice including:

• B3.7.3.4 Detection and management of immune effector cellular therapycomplications…..

• B3.8.2 Training and knowledge of designated pharmacists shallinclude:

• B3.8.2.2 Adverse events including, but not limited to, cytokine release syndrome and neurological toxicities.

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B3.9.1 The Clinical Program shall have access to certified or trained consulting specialists and/or specialist groups from key disciplines who are capable of assisting in the management of patients requiring medical care, including, but not limited to:

INTENSIVE CARE AND NEUROLOGY

The inspector should meet with the neurology lead for the BMT service. Attention should be paid to the knowledge of the neurology department in relation to neurological adverse events associated with IECs.

OTHER SUPPORT SERVICES FOR IECs/CAR T…...

Intensive Care Unit (ICU)• B2.13 There shall be an intensive care

unit or equivalent coverage available

• Close interaction with ICU team

• Education for the ICU team in CAR-T adverse events

• Communication

• Patient monitoring

• Transfer of patients

• NOTE: substantial variation in how ICU is organised; typically difficult to guaranteeexclusive access for CAR-T patients

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AUDITING

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B4.8.3.4 Annual audit of safety endpoints and immune effector cellular therapy toxicity management

OUTCOME ANALYSIS

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B4.7.3.2 For immune effector cells, an endpoint of clinical function asapproved by the Clinical Program Director

STANDARD MANUAL

In addition to overall and treatment-related morbidity and mortality atcertain time points listed below (which are required), examples of clinicalfunction endpoints include:• Time to white cell and platelet recovery,• Incidence of cytokine release syndrome and neurotoxicity• Karnofsky performance status• Target disease response• Disease-free survival.

Date of product administration D0Total number of patients Leukapheresed

Total number of patients received product

Karnofsky performance status (Transplant protocol)

Incidence of cytokine release syndrome all grades

Incidence of Cytokine release syndrome grade 3 or above Incidence of neurotoxicity all grades

Incidence of neurotoxicity grade 3 or above Overall mortality within 30 days

Treatment-related mortality within 30 days

ICU admission within 30 days (TRmorbidity)

Median time to white cell recovery (Days)Time to platelet recovery (Days)Target disease response- CR D100Target disease response- PR D100Relapse/Progression rate D100Overall mortality within 100 days

Treatment-related mortality within 100 daysTarget disease response- CR 1 yearTarget disease response- PR 1 yearTarget disease response- Relapse 1 yearOverall mortality within 1 yearTreatment-related mortality within 1 yearDisease-free survival at 1 yearDisease free survival at 2 yearsDisease free survival at 5 yearsSecondary malignancies

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DATA REPORTING

Conclusion: JACIE’s journey

1998Voluntary initiativeby the transplant

professionals

Mid-2000+Widespread acceptance

among the BMT profession

NowExternal

recognition e.g.Regulations, Payors,

Validation, CELLULAR THERAPY

• CAR T and other IECs best delivered within the framework of an accredited HCT programme

• Quality management and data reporting requirements covered

• EBMT and JACIE expect that most CAR-T activity in Europe will be delivered by experienced allo-HCT centres rolling through the 7th edition

• For a minority of centres that undertake CAR T-cell therapy outside of an accredited allo-HCT programme, options are …• via JACIE accreditation for autologous HCT (e.g. some lymphoma services)• referral to JACIE accredited unit 34

CONCLUSION:CURRENT EBMT & JACIE POSITION…

• 8th edition FACT-JACIE STANDARDS in preparation

• Updated and expanded immune effector cell (IEC) standards anticipated

WHAT’S NEXT?

WHAT WE DO NOT WANT TO BE!•“Tick-box exercise”

• Encouraging health professionals to stop thinking for themselves!

WHAT WE DO NOTWANT TO BE!

•Unnecessary bureaucracy

https://www.cartoonstock.com/cartoonview.asp?catref=forn2693

WHAT WE DO WANT! Impact on patient survival

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WHAT WE DO WANT!Guiding the EBMT community in delivery of CAR-T and other IECs/ATMPs

Acknowledgements

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JACIE Sponsors:

EBMT

ISCT

• JACIE Committee

• JACIE Accreditation

Committee

• JACIE QM Committee

• JACIE National

Representatives

• JACIE Staff• Eoin McGrath, Executive Officer

• JACIE Inspectors

Thankyou!

JACIE Inspectors

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