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Global Perspective on Donor andRecipient Safety: Biovigilance inHematopoietic Cell TransplantationJohn P. Miller, MDPhDVice President and Senior Medical DirectorNational Marrow Donor Program / Be The MatchPublic Forum of the Quebec Biovigilance CommitteeNovember 16, 2016Learning Objectives Understand the nature and goals of the NMDP biovigilance systemfor donors and recipients of hematopoietic progenitor cells (HPC)– Global trends in transplantation– How are HPC donors different from blood, organ and other tissue donors? Describe the NMDP operational processes that support biovigilance– Reporting requirements for donor centers and transplant centers– NMDP reporting requirements domestically and internationally Share incidence data on NMDP biovigilance for donors– Common adverse events– Serious adverse events– Marrow compared to PBSC donors Share best practices moving forward: Emerging cellular therapies2

World Marrow Donor AssociationTransplants by Cell Source Over Time (WMDA)

International Donor and Transplant Sharing (WMDA)Differences Between HPC and Blood DonorsBloodHPCTAnnual # of Events More than 20,000,000 in 30,000 alloHPCT/yrthe US aloneworldwideDonor Æ Patient1:1, 1:2, 1:3 wholebloodUsually 1:1Donor TestingDay of Collection, strictrelease criteriaUp to 30 days prior todonation, flexiblerelease criteriaDonor AssessmentHHQ, limited physicalassessmentHHQ, complete H&P,labs and EKG, CXRand extended testingpossibleMatchingABO/Rh /- RBC AgHLA,gender, ABO, KIR, CCR5etc.Only/best match6

Differences Between HPC andSolid Organ and Tissue TransplantationTissue/Solid OrganHPCTAnnual # of EventsMore than 1,000,000 inthe US alone30,000 alloHPCT/yrworldwideDonor Æ Patient1:many (dozen to 100s)Usually 1:1Donor TestingOften cadaveric: noretesting possibleAlive and well;retesting can be doneDonor AssessmentOften very time limited(as little as hours)Not severely timelimitedMatchingHLA, lower resolutionHLA, allele level 8 lociProductRelease/ExpirationASAP/HoursASAP/Hours or daysor cryopreservation7Differences Between HPC andOrgan, Tissue and Blood Donors HPC donors may be the best or only match for a patientWhile transplantation may be urgent clinically, there istime to do a complete donor health assessmentThe emergence of new blood-borne infectious diseaseswill most likely occur in the setting of the blood andtissue world given the sheer number oftransfusion/transplant eventsTherefore, vigilance efforts should focus on donor andrecipient adverse events and product quality issues toenhance donor and recipient safety8

Key Elements in Donor AE Biovigilance Reported via FormsNet Form 701Medical Quality Assurance Nurses are notified–––– Investigation ensues if appropriateDonor cared for by DC/AC/CC and NMDPNMDP RN staff (TMS/DMS) follow donor to AE resolutionDonor advocacy RN involved if prolonged AEReporting for serious and unexpected AEs plus serious andexpected events of interest as determined by medicaldirector review– vast majority of events reported are non-serious9Key Elements in Recipient AE Biovigilance AE Reporting– TC education regarding what to report, timelines AE training associated with protocols (e.g. 10-CBA) National mtgs (Tandem, NMDP Council, CB Symp) Web resources at marrow.org Event Processing– Reporting via FormsNet2 (phone or email permitted)– Events investigated (NMDP or other stakeholder)– Confirmed events entered into IMS Tracking and Trending– MasterControl tools, reports; staff review10

Recipient Serious Adverse Event (SAE)Reporting for the NMDP Network SAEs associated with PBSC, marrow and cord blood must bereported promptly to NMDP– Report using FormsNet Form 3001 Rationale for seriousness (death, life-threatening,hospitalization, birth defect, permanent impairment ordisability) Event type / severity using CTCAE Terms and Grading AttributionSome events are not NMDP regulatory responsibility and infowill be passed to the appropriate IND holderAll Recipient AE and Product Complaint Reporting viaFormsNetTM2 Effective 4/15/12Cord BloodNMDP INDOther IND, LicensedMononuclearCellsNMDP FacilitatedFormsNet212MarrowPBSCNMDP FacilitatedNMDP Facilitated

Benefits of Recipient AE Reporting System Single source of event entry in a system (FormsNet 2) with whichthe Network is familiar Once event is entered, the NMDP provides event notification to thestakeholders (CBBs, IND holders, etc)– Enhances ability to comply with all reporting obligations– Single source of event submission allows tracking & trending of eventsproducing more timely– Network notification– Root cause investigation and remedial / corrective interventions13What Happens to AE Reports? Investigation by Medical Services RNs and MDsDissemination of Information: Regulatory reporting by NMDP– DPSM (the NMDP’s DSMB) and IRB– FDA when NMDP is the IND holder Otherwise, NMDP passes through the report to the IND holder– HRSA and other US government stakeholders– Other stakeholders: Network announcements and PI letters– Pharma as applicable (e.g. for mobilizing agents) International Reporting– Reporting to World Marrow Donor Association (WMDA) when donor orproduct-related: S(P)EAR14

Incident Management IMS: MasterControlTM– Maintained/administered by NMDP Quality Systems– FDA-compliant, configurable software used to report, resolve, monitor,track and trend QIs– Multiple quality management functions Incident captureRemedial actionInvestigationRisk assessmentCorrective Action/Preventative Action (CAPA)NMDP SOPs guide actions– Definitions of events– Process for incident management15International Efforts in Biovigilance in HPCT WMDA: S(P)EAR reporting for donor AEs and productrelated issues– Consolidates data from independent registries:increases power to detect sentinel AE (Shaw, et al, BMT2013)– Mandatory reporting for accredited registries, standardAE definitions and likely attribution16

WMDA SEAR Reporting Serious/unexpected/medically relevant/previously unknownAny serious event or reaction during anesthesia should be reported.Any serious cardiac complication should be reported.Any serious infection should be reported.Any serious mechanical injury should be reported.Any serious incident in hemostasis should be reportedAny serious (late) effect of marrow or PBSC donation should bereported (e.g. autoimmune, malignancy)Any donor death (from 30 post donation; or at any time if thedonation is implicated)17WMDA S(P)EAR Reporting Processing, labeling, handling and transport errors/problems––––––– Wrong stem cell product transfusedWrong stem cell product receivedSerious problems in transportationDamage to bagInadequate cell dose in the stem cell productClotting or other loss of product viabilityContamination leading to serious infection in recipientAny serious unpredicted transmissible infection– HIV, Hepatitis B, Hepatitis C– Any serious unpredicted non-infectious transmissible disease (e.g. malignant)18

WMDA S(P)EAR Committee Review Reporting requirement for accredited WMDA registriesCommittee has international representation with primary review bynon-reporting peersAnnual reports to community by categoryAlmost 300 Cases reported and reviewed in 2016 with determination:––––Donor or product/patient affectedAdditional information requiredAttribution: both that reported and as determined by committeeEducational value for the transplant community 19The Case that Sparked GRIDGRID will replace themany different methodsof identification usedacross the world todaywith a standard,consistent format20

Biovigilance Reseach: What Have We Learnedand Will Learn About Adverse EventsWhat have we learned: Common Adverse Events (AEs) Marrow vs PBSC donors Serious adverse events (SAE) Related vs. unrelated donorsWhat we will learn: Long term donor follow-up study Malignant, thrombotic and autoimmune diseasesEmerging Cellular TherapiesPulsipher: Blood 2008, 2009 and 2014. CIBMTR Donor Health and Safety Cmte21Common Adverse Events:Frequency of Bone Pain in PBSC Donors7LPH 3RVW 6WDUW RI 0RELOL]DWLRQ 3RVW 'RQDWLRQ

Common Adverse Events:Symptom Score During MobilizationThe Donor Experience Marrow vs PBSC -1 Bone Pain occurred in 80%, irrespective ofdonation typeTiming of bone pain different, mobilization vs. postcollectMost pain was rated as mild or moderateOther symptoms were similar in both groupsBone marrow donors have more prolongedrecovery and lower rates of complete recoveryPulsipher, Blood 201324

The Donor Experience Marrow vs PBSC -2 Overweight and obese PBSC donors have higherrates of grade 2-4 pain in the peri-collection periodFemale donors are more likely to report pain andother symptoms and are less likely to experiencefull recovery, regardless of donation typeOlder marrow donors are less likely to experiencegrades 2-4 skeletal pain in peri-collection period,but they are more likely to have pain at 1 week and1 monthPulsipher, Blood 201325Probability of Complete Recovery:Marrow vs. PBSC26

What About Serious Adverse Events?FDA Criteria Life-threatening or fatal eventInpatient hospitalization or prolongation of existing hospitalizationPersistent or significant disability / incapacityRequired intervention to prevent permanent impairment/damageCongenital anomaly / birth defectOther at physician discretion27Serious Adverse Events in Marrow and PBSC DonorsMethods 5 Physician panel reviewed all events–––––Probable, possible or not AEClassification as serious or not serious (FDA criteria)Attribution as expected or unexpectedMarrow attribution to anesthesia, harvest or unrelatedPBSC attribution to GCSF, apheresis or unrelatedPulsipher M A et al. Blood 2014;123:3655-366328

Serious Adverse Events in Marrow and PBSC DonorsResults: Physician review of Adverse Event Reports 457 AE forms associated with 328 events in 296/2726 marrowdonors (10.9%)1178 AE forms associated with 972 events in 854 PBSC donors(12.6%)Most events were acute and of short durationPulsipher M A et al. Blood 2014;123:3655-366329Serious Adverse Events (SAE):NMDP Experience with Unrelated Donors Rates of SAE were 4x higher with bone marrow donation (2.38%)compared to PBSC donation (0.56%)Rates of unexpected SAE were 3x higher with bone marrowdonation (0.99%) compared to PBSC donation (0.22%)Life threatening events are rare in both marrow (0.26%) and PBSCdonors (0.03%)More life-threatening events, hospitalizations and long term disabilitywith marrow donationThe frequency of SAE are two-fold higher in female donors (Oddsratio for men 0.5)Pulsipher M A et al. Blood 2014;123:3655-366330

Classification of SAEs experienced by BM and PBSC donors.Pulsipher M A et al. Blood 2014;123:3655-3663 2014 by American Society of Hematology

Risk of cancer, autoimmunity, and thrombosis in G-CSF–treated PBSC donors vs BM donors.A Cancer, excluding basal cellB Non-melanoma skinC AutoimmunityD ThrombosisPulsipher M A et al. Blood 2014;123:3655-3663 2014 by American Society of HematologyRisk of Cancer Compared to theGeneral PopulationBone MarrowPBSCObserved Cancer1129Expected Cancer19.8947.95Ratio (obs/exp)0.550.60P value0.0450.004*

Long Term Donor Follow-up StudyPrimary Objective:To describe the long-term incidence of malignant myeloidhematologic disorders in donors who received and in those who didnot receive filgrastimSecondary Objectives:To describe the long-term incidence in donors receiving or notreceiving filgrastim: Malignant hematologic disordersNon-hematologic malignant disordersThrombotic eventsAutoimmune disordersLong Term Donor Follow-up Study Retrospective and Prospective cohorts– 1999-2015 Expected Enrollment:– 10,956 unstimulated marrow donors– 21,172 filgrastim mobilized PBSC donors Enrollment began Oct 2010, now completeCollecting data through 2020 to maximize person-years of follow-up

New Frontier in Biovigilance: Emerging Cellular Therapies Cytotoxic T cells: leukemic-antigen or virusspecific (e.g. CMV, EBV, adenovirus)Tumor vaccinesInduced pluripotent cells (iPC): regeneratedifferent cell linesRegenerative medicine: cell layers (2-D), tissuesand organs 3-DGenomics: screening, diagnosis and treatmentChimeric antigen receptor (CAR) T cells37Summary Serious adverse events are rare, but efforts need to be made tominimize the risk of such eventsAdverse events are more common in bone marrow than PBSCdonorsAdverse events are more common in female donors and recoverytimes are longerThere appears to be little or no increased risk of malignancies,autoimmune disorders or thrombosis in hematopoietic progenitorcell donors

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Nov 16, 2016 · Serious Adverse Events in Marrow and PBSC Donors 29 Results: Physician review of Adverse Event Reports 457 AE forms associated with 328 events in 296/2726 marrow donors (10.9%) 1178 AE forms associated with 972 events in 854 PBSC donors (12.6%) Most events were acute and of sho