Voluntary Accreditation of Immune Effector Cell Programs From Clinical Trials to Licensure and Beyond Phyllis I. Warkentin, MD September 6, 2017
Presentation Outline FACT Standards and Accreditation Program Immune Effector Cell Standards and Accreditation Voluntary FACT Accreditation can Help the Field
FACT Background Founded in 1996 by ASBMT (clinicians, scientists) and ISCT (laboratory scientists) to be their standards setting and accreditation arm to address: Perceived need for minimal standards across the fields of hematology/oncology and stem cell transplantation Mitigate perceived burden of regulatory oversight Develop accreditation process encompassing clinical practices, cell collection, and laboratory services Partner: JACIE to foster international collaboration Partner: NetCord to expand standards for CBB 1998 Partner: CIBMTR to improve data management
FACT s Beginnings
FACT Mission Promote quality patient care and laboratory services Improve transplant / treatment outcomes Foster continued development of cellular therapies Pursued through three core services Standards Accreditation Education
FACT Standards Developed by consensus of experts in the field Clinicians, scientists, technologists, nurses, pharmacists, quality experts, others Based on published medical literature whenever available Public comment; legal and regulatory review; revision: Board approval Minimal requirements; not intended to establish best practices Not prescriptive; allow flexibility; many ways to comply All Standards require: Comprehensive Quality Management program Assessment of relevant end points variable depending on phase of product Safety; efficacy; clinical patient outcomes Compliance with regulations of competent authorities
FACT Accreditation Program Voluntary Programs hold themselves to a higher standard for the benefit of patients Based on compliance with Standards Peer-driven Inspectors: volunteer professionals, active in the field; experts in areas they inspect Inspectors teach, coach, mentor, and learn from inspections Consistent; staff coordinators; Accreditation Committee review International Accredited 182 cellular therapy programs in 7 countries; 224 facilities Accredited 57 cord blood banks in 25 countries and expanding
FACT Educational Activities Workshops, Webinars, On-demand Webcasts Inspector Training; Applicant Preparation Quality Management Series Joint online events with related organizations (NetCord, ASGCT) Back to Basics: Handling Car-T Cell Products Cytokine Release Syndrome Ask a Peer and Ask FACT Accreditation Manual with Guidance Explanation, Evidence, Examples Allied Learning Center (ASBMT, ISCT, etc.) Newsletters
DEVELOPMENT OF IMMUNE EFFECTOR CELL (IEC) STANDARDS AND ACCREDITATION
What are Immune Effector Cells? Broadly defined as cells that are capable of modulating, eliciting, or mitigating an immune response for therapeutic effect Common products Chimeric Antigen Receptor T Cells (CAR-T) Chimeric Antigen Receptor NK Cells (CAR-NK) Cytotoxic T lymphocytes active against viruses or tumor Tumor Infiltrating Lymphocytes (TIL) Therapeutic dendritic cell based vaccines Not included: DLI (unmanipulated donor T Cells) T cells B cells Natural Killer cells Dendritic cells Mesenchymal Stromal cells
Why Standards for Immune Effector Cells? FACT-accredited transplant programs Participation in immune effector cell trials Unique challenges: logistics of delivery and toxicities, particularly Car-T therapies Non-transplant units using immuneeffector cells Lack of clarity: accreditation Regulators Responsibility for approving only safe and effective products for licensure Interest in field s ability to handle toxicities Patient Safety, Outcomes, and Access Drug manufacturers Investment in controlled, safe clinical trials Ensure continued proper handling and use of products when commercially available outside of research study environment Payers Anticipation of drug licensure requests for reimbursement Expectation of good outcomes for covered services; criteria for centers of excellence
FACT Immune Effector Cell Task Force Helen Heslop, MD Chair (ASGCT representative) Baylor College of Medicine Houston, TX Michael Lill, MD Vice-Chair Cedars-Sinai Medical Center Los Angeles, CA Elizabeth Shpall, MD Vice-Chair MD Anderson Cancer Center Houston, TX Carlos Bachier, MD Sarah Cannon BMT Program Nashville, TN Kevin Curran, MD Memorial Sloan-Kettering Cancer Center New York, NY David Maloney, MD, PhD Fred Hutchinson Cancer Research Center Seattle, WA Marcela Maus, MD, PhD (SITC representative) Dana Farber/Harvard Cancer Center Boston, MA Philip McCarthy, MD Roswell Park Cancer Institute Buffalo, NY Sarah Nikiforow, MD, PhD Dana Farber Cancer Institute Boston, MA Jae Park, MD Memorial Sloan-Kettering Cancer Center New York, NY David Porter, MD Penn Medicine Philadelphia, PA Phyllis Warkentin, MD University of Nebraska Medical Center & FACT CMO Omaha, NE
Task Force Accomplishments Reviewed FACT Common Standards for Cellular Therapies Conclusions: FACT Common Standards are generic; applicable to immune effector cell products Some Standards unique to immune effector cell can be delineated Specific unique Standards should apply to IECs regardless of clinical setting Standards should be packaged in a format easily accessible to users regardless of clinical care structure Standards focus on clinical requirements most specific; most variable structures FACT IEC Standards focus on processes, documentation, and oversight, not on scientific validity, vector design, or manufacturing details for any product
FACT Standards FACT Standards for Immune Effector Cells, First Edition Common Standards + Immune Effector Cell-Specific Standards Apply to programs only performing immune effector cell therapy FACT Common Standards for Cellular Therapies, First Edition Standards common to any type of cellular therapy Requirements within included in other sets of Standards Associated accreditation applies to programs not performing hematopoietic cell transplantation or immune effector cell therapy FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration, Edition 6.1 HCT Standards + Immune Effector Cell-Specific Standards Apply to transplant units that may or may not administer immune effector cells
Organization of the Immune Effector Cells: Accommodating Different Models of Care Common Standards Clinical departments separate from transplant (e.g., leukemia service) Immune Effector Cell Standards Hematopoietic Cell Therapy Standards Hematopoietic Stem Cell Transplant Programs
Scope of Immune Effector Cell Standards Processes not science Donor selection and management, collection, labeling, transportation, preparation for administration, administration, management of adverse events, evaluation of clinical outcome Quality Management (QM) program Establishes, maintains, monitors, and implements improvements Includes written SOPs, personnel training and competency, document and record control, GDP, documentation of adverse events, clinical follow up Manufacturing as it occurs under IND in accredited laboratories Control of processes, equipment, supplies, reagents, facilities, personnel Focus: chain of custody, labeling, transportation, storage Education
Standards Specific to Immune Effector Cells Specific IEC Standards are focused on four areas: Third-party manufacturers and importance of identity Cytokine release syndrome and other complications Coordination and education among different departments Data management
Third-Party Manufacturers - I The level of participation of the clinical service in manufacturing an immune effector cell product varies; location varies Regardless of where the product is collected or manufactured, responsibilities must be clearly defined: Ensure and verify chain of custody through multiple handoffs and relabeling from cell collection product administration Programs should have documentation of the quality of the manufacturing laboratory (appropriate regulatory oversight; acceptable standards): A quality audit or report of a quality audit performed by the holder of the Investigational New Drug (IND) application Certificate of Accreditation Licensure
Third-Party Manufacturers - II If cellular therapy products are received directly by the Clinical Program from a third-party manufacturer, the following responsibilities shall be defined at a minimum: Chain of custody of cellular therapy products From donor at collection, through transport/shipping, to recipient at clinical center Clinical program must be confident this is the product intended for this recipient Cellular therapy product storage [secure; temperature] Verification of cellular therapy product identity Management of adverse events
Labeling Challenges Products rely on labeling and identifiers to confirm identity Many products are patient-specific autologous or matched allogeneic donors No real time serological / antigen testing to confirm identity of product to a specific patient Various labeling formats and practices for third party manufactured products Reluctance to use patient identifiers de-identifying / relabeling Frequent use of study numbers not truly unique ; near misses reported IEC Standards require unique product identification; process controls HCT Standards: ISBT128 labeling Recognized by WHO as the global standard for identification and coding of medical products of human origin Unique product identification allows traceability collection administration Does not preclude use of other identifiers, product names, study numbers 667 cellular therapy facilities in 62 countries registered to use ISBT128
Cytokine Release Syndrome - I Procedures shall include detection and management of immune effector cellular therapy complications, including cytokine release syndrome and CNS disease Pharmacies shall have access to formularies adequate to treat cytokine release syndrome and other expected complications of immune effector cell administration Physician, Advance Practice Provider/Professional, and Nurse training and competency must include care interventions to manage complications including: Cytokine release syndrome - Renal and hepatic failure Cardiac dysfunction - Disseminated intravascular coagulation Respiratory distress - Anaphylaxis Neurologic toxicity
Cytokine Release Syndrome II STANDARDS: Clinical Program written guidelines for management of complications [including cytokine-blocking agents and corticosteroids] Regular assessment of the recipient to detect complications, including CRS and neurologic dysfunction Process for rapid escalation of care, increased intensity of monitoring, and relevant workup Timely communication to clinical staff, ICUs, ERs, and pharmacies ASSESSMENTS: Example situation to assess: how to manage CRS after the hospital pharmacy closes? Potential sources of information: document reviews, record reviews, personnel interviews, role playing
Outcome Analysis and Data Management Review outcome analysis and product efficacy for immune effector cells using an endpoint of clinical function as approved by the Clinical Program Director Endpoints defined by clinical trial protocols; reported to IND or sponsor Guidance: should be reviewed by clinical director, reported through QM to program Should collect all data elements in the applicable CIBMTR Cellular Therapy forms Define staff responsible for collecting and reporting data to institutional repositories and CIBMTR Reporting is NOT required Standards require annual audit: Accuracy of clinical data on a periodic basis Safety endpoints and immune effector cellular therapy toxicity management annually
IMMUNE EFFECTOR CELL ACCREDITATION
Why Accreditation for Immune Effector Cells? External validation of quality Assurance to funding organizations and payers Support from general public Regulatory compliance Facilitate peer review Products associated with unexpected, severe adverse reactions, including deaths Accreditation increases preparation, minimize clinical trial set back Various clinical settings; variable QM infrastructure Lack of clarity concerning meaning accreditation for a facility
Accreditation Models Blood and marrow transplant (BMT) clinical sites Involvement of BMT physicians = Clinical Program assumes some or all responsibility for IEC therapy No BMT physician involvement = renting out space and sharing nursing resources = optional, shared or separate accreditation Non-transplant clinical sites No limit to amount of resources sharing May be separate or joint with BMT service Immunotherapy divisions or institutes IEC therapy administered across several different clinical sites under same leadership
Accreditation Schema Renewal Application 3 months to submit checklist Submit Compliance Application Schedule and Conduct Inspection 1 2 3 4 5 6 7 8 9 10 11 12 12 months to submit checklist Month Determine Outcome and Notify Applicant Correct Deficiencies and Award Accreditation Initial Eligibility Application Note: A delay in any of these steps will require shortened timeframe for subsequent steps. Accreditation is valid for three years.
HOW FACT ACCREDITATION SUPPORTS IMMUNE EFFECTOR CELLULAR THERAPY
Promoting Patient Safety Controlled processes for procedure development / staff training enhance: Cell collection and processing to protect the integrity and safety of the product Assurance of identity and chain of custody Safe, effective delivery and administration of the cells evaluation of the patient before and after administration Monitoring, self assessments, deviation management detect noncompliance Rapid identification of and response to adverse events imbedded Evaluation and analysis of outcome data Result for individual patients and follow-up care Aggregate data to detect trends and identify improvement opportunities Improved patient outcomes
Leveraging HPC Transplant Expertise FACT proven expertise in standards and voluntary accreditation program Experience with drafting minimal standards and applying them to clinical and laboratory sites Knowledge of cell therapy as standard of care can be applied to other specialties Collaboration with experts and professional societies is critical Professional in the field are best suited to set Standards Assess relevance and usefulness of existing standards Determine new / specific Standards FACT IEC Standards collaborations: American Society of Gene & Cell Therapy (ASGCT) Society for Immunotherapy of Cancer (SITC) New therapies to patients requires quality and credibility Early introduction of quality management and process control as addressed in Standards helps avoid pitfalls in clinical trials and speeds products to patients
Thank You Resources: Website: www.factwebsite.org Standards, Accreditation Manual, and Quality Handbook: www.factwebsite.org > Store Quality Management Series: www.factwebsite.org> Education and Resources > Quality Management Series