Immune effector cells and JACIE accreditation
Transcript of Immune effector cells and JACIE accreditation
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%
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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
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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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