FDA UpdateFDA Update

Melissa Greenwald, M.D.Melissa Greenwald, M.D.Division of Human TissuesDivision of Human Tissues

AATB Spring MeetingAATB Spring MeetingPlenary SessionPlenary SessionMarch 30, 2009March 30, 2009

Orlando, FLOrlando, FL

Today’s TalkToday’s Talk

• OCTGT Office UpdateOCTGT Office Update• Donor TestingDonor Testing• InspectionsInspections• Regulatory ActionsRegulatory Actions• Deviation ReportsDeviation Reports• Adverse Reaction DataAdverse Reaction Data• Follow-Up on Legal IssuesFollow-Up on Legal Issues

OCTGT UpdateOCTGT Update

• Three new research programsThree new research programs• Retroviral vectorsRetroviral vectors• Tissue safetyTissue safety

• Shyh-Ching LoShyh-Ching Lo• Joydeep GhoshJoydeep Ghosh

• Tolerance and immune regulationTolerance and immune regulation

A new Tissue Laboratory developed under the A new Tissue Laboratory developed under the Division of Cellular & Gene Therapies (DCGT) in Division of Cellular & Gene Therapies (DCGT) in

collaboration with the Division of Human Tissues collaboration with the Division of Human Tissues (DHT) of OCTGT/CBER/FDA:(DHT) of OCTGT/CBER/FDA:

• Promote safety of tissue grafts for transplantationPromote safety of tissue grafts for transplantation• Understand and help validation of various procedures for Understand and help validation of various procedures for

human tissue processinghuman tissue processing• Support evaluation of licensed donor screening testsSupport evaluation of licensed donor screening tests• Develop and apply new methodologies for detection of Develop and apply new methodologies for detection of

microbes in tissues to be used as graftsmicrobes in tissues to be used as grafts• Develop capability of identification and characterization of Develop capability of identification and characterization of

microbes associated with unusual infections or emerging microbes associated with unusual infections or emerging infectious diseasesinfectious diseases

• Collaborate with OBE and support biovigilance study Collaborate with OBE and support biovigilance study relevant to communicable diseases and disease agents in relevant to communicable diseases and disease agents in human tissueshuman tissues

Tissue lab capabilities to be developed:Tissue lab capabilities to be developed:

• Clinical microbiology methodology for detection and Clinical microbiology methodology for detection and characterization of various microbes with tissue safety characterization of various microbes with tissue safety concernsconcerns

• Molecular technologies of rapid detection of specifically Molecular technologies of rapid detection of specifically targeted microbes with high sensitivity using real-time targeted microbes with high sensitivity using real-time quantitative PCR arrays and viral/pathogen chipsquantitative PCR arrays and viral/pathogen chips

• Evaluation and application of high-throughput Evaluation and application of high-throughput sequencing technology for identification of unusual sequencing technology for identification of unusual microbes or emerging infectious disease agentsmicrobes or emerging infectious disease agents

Many of the capabilities of Tissue lab will be supported through outreach and collaborations with various laboratories at FDA

and at the NIH.

Guidances in DevelopmentGuidances in Development• Characterization and Qualification of Cell Banks Characterization and Qualification of Cell Banks

Used in the Production of Cellular and Gene Used in the Production of Cellular and Gene Therapy Products Therapy Products

• Use of Serological Tests on Samples from Donors Use of Serological Tests on Samples from Donors of Whole Blood and Blood Components for of Whole Blood and Blood Components for Transfusion and Donors of Human Cells, Tissues, Transfusion and Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) and Cellular and Tissue-Based Products (HCT/Ps) to Reduce the Risk of Transmission of to Reduce the Risk of Transmission of Trypanosoma cruzi Trypanosoma cruzi infection (OBRR lead)infection (OBRR lead)

Adapted from FDA Annual Guidance Agenda (http://first.fda.gov/fedreg/08/oc0860.pdf)

Guidances in DevelopmentGuidances in Development• Preparation of INDs for Certain Unlicensed Preparation of INDs for Certain Unlicensed

Minimally Manipulated, Unrelated Allogeneic Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Products Placental/Umbilical Cord Blood Products (HPC-C) (HPC-C)

• Clinical Study Design for Early Phase Studies Clinical Study Design for Early Phase Studies of Cellular and Gene Therapies of Cellular and Gene Therapies

• Clinical Study Design Considerations for Clinical Study Design Considerations for Cancer Vaccine Development Cancer Vaccine Development

• Initiation and Conduct of Clinical Trials Using Initiation and Conduct of Clinical Trials Using Cellular Therapies for Cardiac Disease Cellular Therapies for Cardiac Disease

Guidances in DevelopmentGuidances in Development

• Devices Involved in Manufacture, Devices Involved in Manufacture, Storage and Administration of Cellular Storage and Administration of Cellular Products and Tissues Products and Tissues

• Preparation of Investigational Device Preparation of Investigational Device Exemptions and Investigational New Exemptions and Investigational New Drugs for Tissue Engineered and Drugs for Tissue Engineered and Regenerative Medicine Products Regenerative Medicine Products

• Submission of Information for the Submission of Information for the National Xenotransplantation Database National Xenotransplantation Database

RegulationRegulation

• Current Good Manufacturing Practice Current Good Manufacturing Practice and Investigational New Drugs Intended and Investigational New Drugs Intended for Use in Clinical Trials; Final Rule for Use in Clinical Trials; Final Rule 7/15/2008 – effective date 9/15/087/15/2008 – effective date 9/15/08

GuidanceGuidance

• Draft Guidance for Industry: Validation Draft Guidance for Industry: Validation of Growth-Based Rapid Microbiological of Growth-Based Rapid Microbiological Methods for Sterility Testing of Cellular Methods for Sterility Testing of Cellular and Gene Therapy Products 2/11/2008and Gene Therapy Products 2/11/2008

• Guidance for Industry: Content and Guidance for Industry: Content and Review of Chemistry, Manufacturing, Review of Chemistry, Manufacturing, and Control (CMC) Information for and Control (CMC) Information for Human Somatic Cell Therapy Human Somatic Cell Therapy Investigational New Drug Applications Investigational New Drug Applications (INDs) 4/9/2008(INDs) 4/9/2008

GuidanceGuidance• Draft Guidance for Industry: Use of Nucleic Draft Guidance for Industry: Use of Nucleic

Acid Tests to Reduce the Risk of Acid Tests to Reduce the Risk of Transmission of West Nile Virus from Donors Transmission of West Nile Virus from Donors of Whole Blood and Blood Components of Whole Blood and Blood Components Intended for Transfusion and Donors of Intended for Transfusion and Donors of Human Cells, Tissues, and Cellular and Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) 4/25/08Tissue-Based Products (HCT/Ps) 4/25/08• Two FDA-licensed tests for living and Two FDA-licensed tests for living and

cadaveric donorscadaveric donors• All HCT/P donors tested by Individual All HCT/P donors tested by Individual

Donor NATDonor NAT• Comments under reviewComments under review

• Request for Data 7/7/2008Request for Data 7/7/2008• Request for complete data for 2008 WNV Request for complete data for 2008 WNV

season by 1/31/09season by 1/31/09

GuidanceGuidance• Guidance for Industry: CGMP for Phase 1 Guidance for Industry: CGMP for Phase 1

Investigational Drugs 7/15/2008Investigational Drugs 7/15/2008• Well-defined written proceduresWell-defined written procedures• Adequately controlled equipment and Adequately controlled equipment and

manufacturing environmentmanufacturing environment• Accurately and consistently recorded data Accurately and consistently recorded data

from manufacturing (including testing)from manufacturing (including testing)• Draft Guidance for Industry: Considerations Draft Guidance for Industry: Considerations

for Allogeneic Pancreatic Islet Cell Products for Allogeneic Pancreatic Islet Cell Products 5/21/20085/21/2008

GuidanceGuidance

• Guidance for FDA Reviewers and Sponsors: Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Content and Review of Chemistry, Manufacturing, and Control (CMC) Manufacturing, and Control (CMC) Information for Human Gene Therapy Information for Human Gene Therapy Investigational New Drug Applications (INDs) Investigational New Drug Applications (INDs) - 4/9/2008- 4/9/2008

• Draft Guidance for Industry: Potency Tests for Draft Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products - Cellular and Gene Therapy Products - 10/9/200810/9/2008

GuidanceGuidance

• Draft Guidance for Industry: Current Draft Guidance for Industry: Current Good Tissue Practice (CGTP) and Good Tissue Practice (CGTP) and Additional Requirements for Additional Requirements for Manufacturers of Human Cells, Tissues, Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based and Cellular and Tissue-Based Products (HCT/Ps) - 1/16/2009 Products (HCT/Ps) - 1/16/2009

GuidanceGuidance

• Draft Guidance for Industry: Use of Draft Guidance for Industry: Use of Serological Tests to Reduce the Risk of Serological Tests to Reduce the Risk of Transmission of Trypanosoma cruzi Transmission of Trypanosoma cruzi Infection in Whole Blood and Blood Infection in Whole Blood and Blood Components for Transfusion and Components for Transfusion and Human Cells, Tissues, and Cellular and Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) - Tissue-Based Products (HCT/Ps) - 3/26/2009 3/26/2009

GuidanceGuidance

• Draft Chagas guidance, cont.Draft Chagas guidance, cont.• Not for implementationNot for implementation• Notification of intent to make Chagas Notification of intent to make Chagas

Disease (Disease (T. cruziT. cruzi infection) a RCDAD infection) a RCDAD• Makes recommendations for donor Makes recommendations for donor

screening and testingscreening and testing• Docket open for commentsDocket open for comments

Regulations/GuidanceRegulations/Guidance

• http://www.fda.gov/cber/guidelines.htmhttp://www.fda.gov/cber/guidelines.htm • http://www.fda.gov/cber/rules.htmhttp://www.fda.gov/cber/rules.htm

Meetings/WorkshopsMeetings/Workshops• Animal Models for the Treatment of Acute Animal Models for the Treatment of Acute

Radiation Syndrome September 17-18, 2008Radiation Syndrome September 17-18, 2008• Public Workshop: America’s Blood Centers: Public Workshop: America’s Blood Centers:

Blood Establishment Computer Software Blood Establishment Computer Software (BECS) Conference July 10-11, 2008(BECS) Conference July 10-11, 2008

• FDA Workshop to Consider Approaches to FDA Workshop to Consider Approaches to Reduce the Risk of Transfusion-Transmitted Reduce the Risk of Transfusion-Transmitted Babesiosis in the United States September Babesiosis in the United States September 12, 200812, 2008

Meetings/WorkshopsMeetings/Workshops

• Blood Products Advisory Committee (1 April Blood Products Advisory Committee (1 April 2009); one topic will discuss blood donor 2009); one topic will discuss blood donor screening, and testing donors of human cells, screening, and testing donors of human cells, tissues, and cellular and tissue-based tissues, and cellular and tissue-based products (HCT/Ps) for hepatitis B virus products (HCT/Ps) for hepatitis B virus infection by nucleic acid testinginfection by nucleic acid testing

• http://www.fda.gov/cber/advisory/bp/http://www.fda.gov/cber/advisory/bp/bp0409.htmbp0409.htm

Meetings/WorkshopsMeetings/Workshops

• http://www.fda.gov/cber/minutes/workshhttp://www.fda.gov/cber/minutes/workshop-min.htmop-min.htm

• http://www.fda.gov/cber/scireg.htmhttp://www.fda.gov/cber/scireg.htm

HCT/P Donor Tests for RCDADsHCT/P Donor Tests for RCDADs• Updated listing of all Updated listing of all

available donor screening available donor screening tests and appropriate tests and appropriate specimens (originally specimens (originally posted Feb 2007) at: posted Feb 2007) at: http://www.fda.gov/cber/tihttp://www.fda.gov/cber/tissue/prod.ssue/prod.htm#approvedhtm#approved

• Specific testing Specific testing requirements listed at: requirements listed at: http://www.fda.gov/cber/tihttp://www.fda.gov/cber/tissue/hctptestreq.htmssue/hctptestreq.htm

HRSA RFI on Vascularized HRSA RFI on Vascularized Composite AllograftsComposite Allografts

• HRSA seeking comment on whether HRSA seeking comment on whether vascularized composite allografts should be vascularized composite allografts should be included in definition of organincluded in definition of organ

• See Request for Information (RFI) at:See Request for Information (RFI) at: http://http://www.gpoaccess.gov/fr/index.htmlwww.gpoaccess.gov/fr/index.html

• Public meeting April 4, 2008 at Parklawn Public meeting April 4, 2008 at Parklawn Bldg, Rockville MDBldg, Rockville MD

• Comment period closed May 2, 2008Comment period closed May 2, 2008• Contact HRSA for more info:Contact HRSA for more info:

301-443-7577301-443-7577

General Testing RequirementsGeneral Testing Requirements

• 1271.80(c) Tests. You must test using 1271.80(c) Tests. You must test using appropriate FDA-licensed, approved, or appropriate FDA-licensed, approved, or cleared donor screening tests, in cleared donor screening tests, in accordance with the manufacturer’s accordance with the manufacturer’s instructions, to adequately and instructions, to adequately and appropriately reduce the risk of appropriately reduce the risk of transmission of relevant communicable transmission of relevant communicable diseases.diseases.

Maximum specimen storage claims in Maximum specimen storage claims in selected HCT/P donor screening testsselected HCT/P donor screening tests

• HCV NAT:HCV NAT:• COBAS Ampliscreen HCV Test, version 2.0:COBAS Ampliscreen HCV Test, version 2.0:

Living donor (LD) specimens, maximum time Living donor (LD) specimens, maximum time frozen is one month; cadaveric specimens (CAD) frozen is one month; cadaveric specimens (CAD) up to 72 hours.up to 72 hours.

• COBAS Taqscreen MPXCOBAS Taqscreen MPX: LD maximum time : LD maximum time frozen 30 days, No current CAD claimfrozen 30 days, No current CAD claim

• Procleix HIV-1/HCV AssayProcleix HIV-1/HCV Assay: LD 5 days at 2-8; : LD 5 days at 2-8; “longer periods of time at </= -20 degrees C” [a “longer periods of time at </= -20 degrees C” [a specific time-frame has not been validated]; CAD specific time-frame has not been validated]; CAD “long term storage of plasma at </= -20 has not “long term storage of plasma at </= -20 has not been established”been established”

• Procleix Ultrio AssayProcleix Ultrio Assay: LD up to 6 months frozen, : LD up to 6 months frozen, CAD up to 2 weeksCAD up to 2 weeks

Maximum specimen storage claims in Maximum specimen storage claims in selected HCT/P donor screening testsselected HCT/P donor screening tests

• HIV NAT: same as for HCV NAT HIV NAT: same as for HCV NAT • COBAS Ampliscreen HIV-1 Test has COBAS Ampliscreen HIV-1 Test has

same storage claim as the same storage claim as the Ampliscreen HCV test – up to one Ampliscreen HCV test – up to one month month

• all other tests are the sameall other tests are the same

Antibody Test Storage ClaimsAntibody Test Storage Claims

• Many have language similar to belowMany have language similar to below**::

For cadaveric specimens, follow general standards For cadaveric specimens, follow general standards and/or regulations for collection, storage and and/or regulations for collection, storage and handling. Cadaveric specimens may be stored frozen handling. Cadaveric specimens may be stored frozen (-20°C or colder) or stored for up to 2 days at 2 - 8°C. (-20°C or colder) or stored for up to 2 days at 2 - 8°C. If storage periods greater than 2 days at 2 - 8°C are If storage periods greater than 2 days at 2 - 8°C are anticipated, the serum should be removed from the anticipated, the serum should be removed from the clot to avoid hemolysis and stored frozen.clot to avoid hemolysis and stored frozen.

* Abbott PRISM HBsAg AssayAbbott PRISM HBsAg Assay

Antibody Test Storage ClaimsAntibody Test Storage Claims

Ortho HCV and Chagas ELISA tests (Ab) Ortho HCV and Chagas ELISA tests (Ab) • Cadaveric specimens may be stored for up to 10 Cadaveric specimens may be stored for up to 10

days at 2-8°C and up to 4 weeks at –20°C days at 2-8°C and up to 4 weeks at –20°C undergoing 5 freeze/thaw cycles. Store specimens in undergoing 5 freeze/thaw cycles. Store specimens in appropriately qualified freezers. Specimens may be appropriately qualified freezers. Specimens may be frozen and thawed up to 5 times. Mix specimen frozen and thawed up to 5 times. Mix specimen thoroughly after thawing and before testing. thoroughly after thawing and before testing.

• Studies have demonstrated that specimens may be Studies have demonstrated that specimens may be shipped at ambient temperature (up to 37°C) for up to shipped at ambient temperature (up to 37°C) for up to seven days or refrigerated (2 to 8°C) for up to seven seven days or refrigerated (2 to 8°C) for up to seven days. Upon arrival, specimens should be stored at 2 days. Upon arrival, specimens should be stored at 2 to 8°C. For shipments requiring extensive transit to 8°C. For shipments requiring extensive transit times (greater than seven days), specimens should times (greater than seven days), specimens should be kept frozen (-20°C or below). be kept frozen (-20°C or below).

FY08 HCT/P FY08 HCT/P Inspections AccomplishedInspections Accomplished

Type of HCT/P Type of HCT/P establishmentestablishment

# Inspections # Inspections

AccomplishedAccomplished

Hours/Hours/

InspectionInspection

Reproductive tissuesReproductive tissues 158158 42.442.4

Cord blood stem cellsCord blood stem cells

Peripheral blood stem cellsPeripheral blood stem cells

1919 31.731.7

All other HCT/Ps All other HCT/Ps

(e.g. (e.g. musculoskeletal, ocular, musculoskeletal, ocular, recovery, distributors)recovery, distributors)

213213 34.434.4

TotalTotal 383*383* 37.537.5

*Sum of individual inspections do not equal total due to some inspections that were conducted for products in multiple categories

FY08 HCT/P Inspection Classifications

Type of HCT/P Type of HCT/P establishmentestablishment

NAINAI VAIVAI OAIOAI

Reproductive tissuesReproductive tissues 106106 4040 1010

Cord blood stem cellsCord blood stem cells

Peripheral blood stem Peripheral blood stem cellscells

1515 44 00

All other HCT/Ps All other HCT/Ps

(e.g. (e.g. musculoskeletal, musculoskeletal, ocular, recovery, ocular, recovery, distributors)distributors)

164164 4646 11

TotalTotal 285285 9090 1111

FDA Form 483FDA Form 483

• ““This document lists observations made by the FDA This document lists observations made by the FDA representative(s) during the inspection of your facility. representative(s) during the inspection of your facility. They are inspectional observations, and do not They are inspectional observations, and do not represent a final agency determination regarding your represent a final agency determination regarding your compliance. If you have an objection regarding an compliance. If you have an objection regarding an observation, or have implemented, or plan to observation, or have implemented, or plan to implement, corrective action in response to an implement, corrective action in response to an observation, you may discuss the objection or action observation, you may discuss the objection or action with the FDA representative(s) during the inspection with the FDA representative(s) during the inspection or submit this information to FDA at the address or submit this information to FDA at the address above….”above….”

OAI/VAI/NAI?OAI/VAI/NAI?

• OAI – Official Action Indicated – objectionable OAI – Official Action Indicated – objectionable conditions found that warrant actionconditions found that warrant action

• VAI – Voluntary Action Indicated – VAI – Voluntary Action Indicated – objectionable conditions found but do not objectionable conditions found but do not meet the threshold for regulatory actionmeet the threshold for regulatory action

• NAI – No Action Indicated – no objectionable NAI – No Action Indicated – no objectionable conditions found (generally no FDA-483)conditions found (generally no FDA-483)

• http://www.fda.gov/ora/inspect_ref/fmd/http://www.fda.gov/ora/inspect_ref/fmd/fmd86.htmfmd86.htm

FY08 HCT/P FY08 HCT/P Inspection ResultsInspection Results

• Approx. 30% of HCT/P inspections Approx. 30% of HCT/P inspections resulted in issuance of Form FDA-483s; resulted in issuance of Form FDA-483s;

• Consistent with FY07 and FY06. Consistent with FY07 and FY06.

Inspectional Observations:Inspectional Observations:Storage and DistributionStorage and Distribution

• Failure to store HCT/Ps at appropriate temperatures; Failure to store HCT/Ps at appropriate temperatures; establish acceptable temperature limits; and/or establish acceptable temperature limits; and/or maintain and record storage temperatures 21 CFR maintain and record storage temperatures 21 CFR 1271.260 (b) and (e)1271.260 (b) and (e)• Storage room temperatures are not Storage room temperatures are not

recordedrecorded• Freezer did not have a functioning Freezer did not have a functioning

recording device and was not equipped recording device and was not equipped with an alarm. The freezer temperature is with an alarm. The freezer temperature is not recorded or monitored after normal not recorded or monitored after normal operating hoursoperating hours

• Temperature monitoring logs not reviewed Temperature monitoring logs not reviewed prior to removal/transfer of grafts as prior to removal/transfer of grafts as required in the SOPrequired in the SOP

Inspectional Observations:Inspectional Observations:ProcessorsProcessors

• Failure to maintain facility in good state of repair 21 Failure to maintain facility in good state of repair 21 CFR 1271.190(a)CFR 1271.190(a)• Several processing rooms have damage to the Several processing rooms have damage to the

walls – areas of damage show exposed dry wall walls – areas of damage show exposed dry wall below the level of the paper layerbelow the level of the paper layer

• Failure to maintain documentation of equipment Failure to maintain documentation of equipment maintenance, cleaning, sanitization and calibration 21 maintenance, cleaning, sanitization and calibration 21 CFR 1271. 200(e)CFR 1271. 200(e)• Cleaning of equipment was not documented. Cleaning of equipment was not documented.

There were no records of cleaning from 1/2006 – There were no records of cleaning from 1/2006 – 3/20083/2008

Inspectional Observations:Inspectional Observations:Processors - 2Processors - 2

• Failure to process HCT/Ps in a way that does Failure to process HCT/Ps in a way that does not increase the risk of introduction, not increase the risk of introduction, transmission or spread of communicable transmission or spread of communicable disease 21 CFR 1271.220(a)disease 21 CFR 1271.220(a)• There were five occurrences where There were five occurrences where

containers holding tissue from two different containers holding tissue from two different donors were opened at the same time in donors were opened at the same time in the processing hood. (Note – a cross the processing hood. (Note – a cross contamination event had been contamination event had been documented)documented)

Inspectional Observations:Inspectional Observations:Donor TestingDonor Testing

• Failure to perform testing for Failure to perform testing for communicable disease agents communicable disease agents according to the manufacturer’s according to the manufacturer’s instructions 21 CFR 1271.80(c)instructions 21 CFR 1271.80(c)• Cadaveric samples tested by NAT Cadaveric samples tested by NAT

assay were routinely tested using a assay were routinely tested using a 1:5 dilution. The package insert 1:5 dilution. The package insert instructs that cadaveric donors be instructs that cadaveric donors be tested “neat.”tested “neat.”

Regulatory ActionsRegulatory Actions

• Regulatory Actions IssuedRegulatory Actions Issued• 1 Warning Letter (repro)1 Warning Letter (repro)• 1 Untitled Letter (repro)1 Untitled Letter (repro)• 1 Untitled Letter –website/stem cell 1 Untitled Letter –website/stem cell

treatment – part of our internet treatment – part of our internet surveillance surveillance

FY08 HCT/P Regulatory FY08 HCT/P Regulatory Actions: Deviations CitedActions: Deviations Cited

• Failure to test specimens from anonymous or Failure to test specimens from anonymous or directed reproductive donors using appropriate directed reproductive donors using appropriate FDA-FDA-licensed, approved, or cleared donor screening licensed, approved, or cleared donor screening teststests, in accordance with the manufacturer's , in accordance with the manufacturer's

instructionsinstructions 21 CFR 1271.80(c).21 CFR 1271.80(c). • Failure to screen an anonymous or directed Failure to screen an anonymous or directed

reproductive donor of cells or tissue by reviewing the reproductive donor of cells or tissue by reviewing the donor's relevant medical records for risk factors for, donor's relevant medical records for risk factors for, and clinical evidence of, relevant communicable and clinical evidence of, relevant communicable disease agents and diseases 21 CFR 1271.75(a). disease agents and diseases 21 CFR 1271.75(a).

Regulatory Actions - 2Regulatory Actions - 2

• Failure to establish and maintain procedures for all steps that are performed in testing, screening, determining donor eligibility, and complying with all other requirements of Subpart C "Donor Eligibility" in 21 CFR Part 1271. "Establish and maintain" means define, document, and implement; then follow, review, and as needed, revise on an ongoing basis [21 CFR 1271.47(a)].

• The firm's standard operating procedures did not address all steps required for donor screening and determining donor eligibility, including, but not limited to: (1) donor screening for risk factors for, or clinical evidence of relevant communicable disease agents and diseases; and (2) the criteria used to determine donor eligibility and ineligibility.

HCT/P Deviation ReportingHCT/P Deviation Reporting

FY06FY06 FY07FY07 FY08FY08

ReportableReportable 144144 153153 223223

Electronic Electronic ReportsReports

100 100

(69%)(69%)

118 118

(77%)(77%)

164 164

(74%)(74%)

Non-ReportableNon-Reportable 7676 4848 6363

Total ReportsTotal Reports 220220 201201 286286

HCT/P Deviation ReportsHCT/P Deviation ReportsProducts InvolvedProducts Involved

ProductProduct FY06FY06 FY07FY07 FY08FY08

Peripheral Blood Stem Peripheral Blood Stem CellsCells 7171 9898 109109

Cornea/ScleraCornea/Sclera 5151 3535 4444

SkinSkin 66 66 2727

MusculoskeletalMusculoskeletal 2121 1414 2626

Somatic CellsSomatic Cells 00 11 1919

Donor LeukocytesDonor Leukocytes 66 1010 1212

Cord Blood Stem CellsCord Blood Stem Cells 22 44 44

HCT/P Deviations ReportedHCT/P Deviations Reported

Reportable HCT/P Reportable HCT/P DeviationsDeviations

FY 05FY 05 FY 06FY 06 FY 07FY 07 FY 08FY 08

Donor EligibilityDonor Eligibility 88 3232 2424 3737

Donor ScreeningDonor Screening   00 1212 88 1717

Donor TestingDonor Testing 00 3333 5454 5454

Environmental ControlEnvironmental Control 00 11 22 00

Supplies and ReagentsSupplies and Reagents   00 33 66 11

RecoveryRecovery   00 22 88 88

ProcessingProcessing   00 1414 1717 6868

Labeling ControlLabeling Control 11 22 11 22

StorageStorage   00 11 00 00

Receipt, Pre-Dist., Dist.Receipt, Pre-Dist., Dist. 44 4343 3232 3636

TotalTotal 1313 143143 152152 223223

Non-ReportableNon-Reportable 1515 7777 4848 6363

HCT/P Deviation Reports HCT/P Deviation Reports Non-Reportable EventsNon-Reportable Events

• No products were distributedNo products were distributed• Not associated with disease transmission or Not associated with disease transmission or

contaminationcontamination• Not related to core GTPNot related to core GTP• Product released under urgent medical needProduct released under urgent medical need• Product not subject to HCT/P deviation reportingProduct not subject to HCT/P deviation reporting

• Reproductive tissueReproductive tissue• Unrelated Allogeneic Stem CellsUnrelated Allogeneic Stem Cells

• Reporting establishment is not an HCT/P Reporting establishment is not an HCT/P manufacturermanufacturer

HCT/P Deviation Reports HCT/P Deviation Reports Non-Reportable EventsNon-Reportable Events

• Positive pre-implant culture is in general Positive pre-implant culture is in general not reportable as a deviationnot reportable as a deviation• Unless a complaint results in an Unless a complaint results in an

investigation that reveals a departure investigation that reveals a departure from GTPs orfrom GTPs or

• If the recipient had an adverse If the recipient had an adverse reaction then might be reported as an reaction then might be reported as an adverse reaction not HCT/P deviationadverse reaction not HCT/P deviation

HCT/P Deviation Reporting FY08HCT/P Deviation Reporting FY08

  HCT/P Deviation CodeHCT/P Deviation CodeCellular Cellular HCT/PHCT/P

Tissue Tissue HCT/PHCT/P TotalTotal

Donor EligibilityDonor Eligibility 44 3333 3737 16.6%16.6%

Donor ScreeningDonor Screening 22 1515 1717 7.6%7.6%

Donor TestingDonor Testing 4242 1212 5454 24.2%24.2%

Environmental ControlEnvironmental Control 00 00 00 0.0%0.0%

Supplies and ReagentsSupplies and Reagents 11 00 11 0.4%0.4%

RecoveryRecovery 88 00 88 3.6%3.6%

Processing and Processing and Processing ControlsProcessing Controls 5050 1818 6868 30.5%30.5%

Labeling ControlsLabeling Controls 00 22 22 0.9%0.9%

StorageStorage 00 00 00 0.0%0.0%

Receipt, Pre-Distribution, Receipt, Pre-Distribution, Shipment & DistributionShipment & Distribution 3333 33 3636 16.1%16.1%

TotalTotal 140140 8383 223223 100%100%

Tissue HCT/P ReportsTissue HCT/P Reports

• Donor Eligibility – 33 reportsDonor Eligibility – 33 reports• Donor accepted when risk factors, clinical Donor accepted when risk factors, clinical

evidence or physical evidence identified – evidence or physical evidence identified – 1818

• Donor accepted when reactive for relevant Donor accepted when reactive for relevant communicable disease – 4communicable disease – 4

• Donor incorrectly evaluated for plasma Donor incorrectly evaluated for plasma dilution – 10dilution – 10

• Donor testing not performed or Donor testing not performed or documented - 1documented - 1

Tissue HCT/P Reports - 2Tissue HCT/P Reports - 2

• Processing and process controls – 18Processing and process controls – 18• HCT/P contaminated, potentially HCT/P contaminated, potentially

contaminated or cross contaminated – 17contaminated or cross contaminated – 17• In-process controls inadequate – 1In-process controls inadequate – 1

• Microorganisms involved:Microorganisms involved:• Bacillus, Candida, Clostridium, Bacillus, Candida, Clostridium,

Enterobacter, Group D Enterococcus, Enterobacter, Group D Enterococcus, Staphylococcus, ProteusStaphylococcus, Proteus

Tissue HCT/P Reports - 3Tissue HCT/P Reports - 3

• Donor Screening – 15Donor Screening – 15• Donor screening not performed or Donor screening not performed or

documented – 1documented – 1• Donor screening (medical history Donor screening (medical history

interview) performed incorrectly interview) performed incorrectly (incomplete or inaccurate) – 13(incomplete or inaccurate) – 13

• Donor screening (medical record Donor screening (medical record review) performed incorrectly review) performed incorrectly (incomplete or inaccurate) - 1(incomplete or inaccurate) - 1

Classified RecallsClassified RecallsFY 2007FY 2007

HCT/PHCT/P

RecallsRecalls

CBER Total CBER Total Recalls Recalls

(all products)(all products)

FY 07 Class IFY 07 Class I 77 77

FY 07 Class IIFY 07 Class II 1515 10411041

FY 07 Class IIIFY 07 Class III 00 381381

Classified RecallsClassified RecallsFY 2008*FY 2008*

HCT/PHCT/P

RecallsRecalls

CBER Total CBER Total Recalls Recalls

(all products)(all products)

FY 08 Class IFY 08 Class I 33 44

FY 08 Class IIFY 08 Class II 1111 950950

FY 08 Class IIIFY 08 Class III 77 345345

* This table does not include 3 “mixed class” recalls

FY 2008 Class I FY 2008 Class I HCT/P RecallsHCT/P Recalls

• Donors met all DE requirements using Donors met all DE requirements using diagnosticdiagnostic HBsAg and HBcAb tests. Re- HBsAg and HBcAb tests. Re-testing of donors using FDA licensed donor testing of donors using FDA licensed donor screening tests revealed three donors screening tests revealed three donors reactive (confirmed positive) for HBsAgreactive (confirmed positive) for HBsAg• 2 recalls2 recalls

• Clostridium perfringens Clostridium perfringens infection in recipient.infection in recipient.

HCT/P RecallsHCT/P Recalls

0

5

10

15

20

25

30

35

40

45

FY00 FY01 FY02 FY03 FY04 FY05 FY06 FY07 FY08

Class I

Class II

Class III

Adverse Reaction DataAdverse Reaction Data

Adverse Reactions ReportedAdverse Reactions Reported** by Tissue Typeby Tissue Type

**Numbers reflect reports, not confirmed cases. Most reports are of routine post-op Numbers reflect reports, not confirmed cases. Most reports are of routine post-op infections and it is difficult to conclusively distinguish if allograft-related.infections and it is difficult to conclusively distinguish if allograft-related.

** ** 2008 includes reports received 1/1 through 12/11/ 20082008 includes reports received 1/1 through 12/11/ 2008

Tissue typeTissue type CY 2005CY 2005 CY 2006CY 2006 CY 2007CY 2007 CY 2008**CY 2008**

Total InfectionsTotal Infections 3535 9898 9191 7777

BoneBone 99 2626 2121 99

Musculoskeletal Musculoskeletal TissueTissue 44 2121 3838 2929

SkinSkin 1212 2222 1818 1818

EyeEye 88 2727 1212 1616

CardiacCardiac 11 11 11 22

Blood VesselBlood Vessel 11 11 00 11

Tissue, NOSTissue, NOS 00 00 11 22

Reported Adverse Reported Adverse Reactions by OutcomeReactions by Outcome

Type of eventType of event 20052005** 20062006 20072007 2008**2008** TotalTotal

Infectious AEInfectious AE 3535 9898 9191 7777 301301

Non-Infectious Non-Infectious AEAE 2020 3232 2727 2525 104104

No AENo AE 2020 1717 66 1818 6161

TotalTotal 7575 147147 124124 120120 466466

* * Data for 2005 includes only reports after May 25 Data for 2005 includes only reports after May 25

** ** Includes reports received 1/1/08-12/16/2008Includes reports received 1/1/08-12/16/2008

Reported Adverse Reactions Reported Adverse Reactions by Reported Organismby Reported Organism

** Includes reports received 1/1/08-12/16/2008** Includes reports received 1/1/08-12/16/2008

20062006 20072007 20082008**** OrganismOrganism

5757 6363 4545 BacteriaBacteria

66 55 1212 FungiFungi

2323 88 33 VirusVirus

33 CJDCJD

1212 1515 1414 UnknownUnknown

9898 9191 7777 TotalTotal

Biomedical Tissue Services (BTS)Biomedical Tissue Services (BTS)Order to Cease and Retain HCT/PsOrder to Cease and Retain HCT/Ps

• Immediately cease manufacturing operations and Immediately cease manufacturing operations and retain HCT/Ps.retain HCT/Ps.

• To BTS and its CEO and Executive Director, Michael To BTS and its CEO and Executive Director, Michael Mastromarino, D.D.S.Mastromarino, D.D.S.

• After initially focusing efforts on assessing the safety After initially focusing efforts on assessing the safety of distributed tissue and facilitating recalls, FDA of distributed tissue and facilitating recalls, FDA determined that the violations uncovered at BTS, determined that the violations uncovered at BTS, because of their serious nature, constitute a danger because of their serious nature, constitute a danger to health and took this unprecedented actionto health and took this unprecedented action

• Order to Cease Manufacturing and to Retain HCT/Ps Order to Cease Manufacturing and to Retain HCT/Ps issued January 31, 2006issued January 31, 2006

• www.fda.gov/cber/compl/bts013106.htm www.fda.gov/cber/compl/bts013106.htm

BTS OrderBTS Order• Despite records maintaining otherwise:Despite records maintaining otherwise:

• The firm inadequately screened donors for The firm inadequately screened donors for risk factors for, or clinical evidence of, risk factors for, or clinical evidence of, relevant communicable disease agents and relevant communicable disease agents and diseases;diseases;

• FDA found numerous instances where death FDA found numerous instances where death certificates maintained in BTS’ files were at certificates maintained in BTS’ files were at variance with the death certificates FDA variance with the death certificates FDA obtained from the state where the death obtained from the state where the death occurred:occurred:

• Cause, place, and time of death, and the Cause, place, and time of death, and the identity of next of kin.identity of next of kin.

• FDA continued to work with other federal, state FDA continued to work with other federal, state and local authoritiesand local authorities

CDC: MMWR CDC: MMWR Brief Report May 26, 2006Brief Report May 26, 2006

• ““Investigation into Recalled Human Tissue for Investigation into Recalled Human Tissue for Transplantation---United States, 2005--2006.”Transplantation---United States, 2005--2006.”

• Approximately 25,000 BTS-recovered tissue Approximately 25,000 BTS-recovered tissue products distributed to all 50 states and products distributed to all 50 states and internationallyinternationally

• FDA and CDC continue to investigate reports FDA and CDC continue to investigate reports of BTS recipients who have undergone of BTS recipients who have undergone screening and tested positive for one of the screening and tested positive for one of the four tested diseasesfour tested diseases

• Some positive results would be expected in Some positive results would be expected in any U.S. population tested (prevalence data any U.S. population tested (prevalence data provided)provided)

MMWR cont..MMWR cont..

• Relationship between implanted BTS Relationship between implanted BTS tissue and positive test results reported tissue and positive test results reported to FDA and CDC is difficult to ascertain to FDA and CDC is difficult to ascertain because of inaccurate BTS donor because of inaccurate BTS donor records and, in some cases, the records and, in some cases, the absence of properly linked donor absence of properly linked donor samples.samples.

BTS UpdateBTS Update• In March 2008, Michael Mastromarino pleaded guilty In March 2008, Michael Mastromarino pleaded guilty

in Brooklyn Supreme Court to body stealing, forgery, in Brooklyn Supreme Court to body stealing, forgery, grand larceny and enterprise corruption and was grand larceny and enterprise corruption and was sentenced to 18 to 54 years. He is serving a sentenced to 18 to 54 years. He is serving a concurrent sentence of 25 to 58 years after pleading concurrent sentence of 25 to 58 years after pleading guilty to similar changes in Philadelphia.guilty to similar changes in Philadelphia.

• Co-defendant Lee Cruceta pleaded guilty to Co-defendant Lee Cruceta pleaded guilty to conspiracy, taking part in a corrupt organization, conspiracy, taking part in a corrupt organization, abuse of a corpse and 244 counts each of theft and abuse of a corpse and 244 counts each of theft and forgery in Philadelphia and also has pleaded guilty forgery in Philadelphia and also has pleaded guilty to related charges in Brooklyn and negotiated pleas to related charges in Brooklyn and negotiated pleas to serve concurrent sentences of 6½ to 20 years. to serve concurrent sentences of 6½ to 20 years.

• Co-defendant Chris Aldorasi was found guilty of Co-defendant Chris Aldorasi was found guilty of enterprise corruption and other criminal counts in enterprise corruption and other criminal counts in Brooklyn and sentenced to 9 to 27 years.Brooklyn and sentenced to 9 to 27 years.

BTS Update - 2BTS Update - 2

• Co-defendant Joseph Nicelli has yet to stand trial in Co-defendant Joseph Nicelli has yet to stand trial in BrooklynBrooklyn

• On December 12, 2008, Jason Gano, a former On December 12, 2008, Jason Gano, a former funeral director in Rochester, NY, was found guilty of funeral director in Rochester, NY, was found guilty of 17 counts each of opening graves, body stealing, and 17 counts each of opening graves, body stealing, and unlawful dissection, as well as one count of scheming unlawful dissection, as well as one count of scheming to defraud. He faces up to 20 years in prison when to defraud. He faces up to 20 years in prison when he is sentenced.he is sentenced.

• Six others are expected to stand trial in RochesterSix others are expected to stand trial in Rochester• FDA will continue to work cooperatively with other FDA will continue to work cooperatively with other

Federal, State and local authoritiesFederal, State and local authorities

Donor Referral Services (DRS) Order to Donor Referral Services (DRS) Order to Cease Manufacturing and Retain HCT/PsCease Manufacturing and Retain HCT/Ps

• Immediately cease manufacturing operations Immediately cease manufacturing operations and retain HCT/Ps.and retain HCT/Ps.

• To DRS and its Owner, Philip GuyettTo DRS and its Owner, Philip Guyett• FDA determined that the violations uncovered FDA determined that the violations uncovered

at DRS, because of their serious nature, at DRS, because of their serious nature, constitute a danger to health and took actionconstitute a danger to health and took action

• Order to Cease Manufacturing and to Retain Order to Cease Manufacturing and to Retain HCT/Ps issued 18 August, 2006HCT/Ps issued 18 August, 2006

• http://www.fda.gov/cber/compl/drs081806.htm http://www.fda.gov/cber/compl/drs081806.htm

DRS OrderDRS Order

• FDA found numerous instances where FDA found numerous instances where information provided by DRS to a tissue information provided by DRS to a tissue processor was at variance with the processor was at variance with the death certificates FDA obtained from death certificates FDA obtained from the state where the death occurred:the state where the death occurred:

• Cause, place, and time of Cause, place, and time of deathdeath

DRS Public Health NotificationDRS Public Health Notification

• August 30, 2006August 30, 2006• FDA and CDC strongly recommended health FDA and CDC strongly recommended health

care providers inform all patients that care providers inform all patients that received tissue initially recovered by DRS received tissue initially recovered by DRS and offer access to communicable disease and offer access to communicable disease testingtesting

• Distributing firms had already voluntarily Distributing firms had already voluntarily recalled tissue in inventoryrecalled tissue in inventory

• Where FDA had previously identified specific Where FDA had previously identified specific cases of concern, the firms cooperated fully cases of concern, the firms cooperated fully in efforts to inform patients and offer testing in in efforts to inform patients and offer testing in those cases those cases

DRS UpdateDRS Update

• On March 9, 2009, Philip Guyett pleaded On March 9, 2009, Philip Guyett pleaded guilty in U.S District Court in Raleigh, North guilty in U.S District Court in Raleigh, North Carolina to three counts of mail fraudCarolina to three counts of mail fraud

• He is scheduled to be sentenced June 1, He is scheduled to be sentenced June 1, 2009, and faces up to 60 years in prison and 2009, and faces up to 60 years in prison and $750,000 in fines$750,000 in fines

• FDA continues to investigate DRS working FDA continues to investigate DRS working with other federal, state and local authoritieswith other federal, state and local authorities

CBER InformationCBER Information

• Web siteWeb site• http://www.fda.gov/cberhttp://www.fda.gov/cber • http://www.fda.gov/cber/tiss.htmhttp://www.fda.gov/cber/tiss.htm

• E-mailE-mail• Manufacturers: matt@cber.fda.govManufacturers: matt@cber.fda.gov• Consumers, health care: Consumers, health care:

octma@cber.fda.govoctma@cber.fda.gov• PhonePhone

• 301-827-1800301-827-1800