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FDA Update. Melissa Greenwald, M.D. Division of Human Tissues AATB Spring Meeting Plenary Session March 30, 2009 Orlando, FL. Today’s Talk. OCTGT Office Update Donor Testing Inspections Regulatory Actions Deviation Reports Adverse Reaction Data Follow-Up on Legal Issues.

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FDA Update

Melissa Greenwald, M.D.

Division of Human Tissues

AATB Spring Meeting

Plenary Session

March 30, 2009

Orlando, FL


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Today’s Talk

  • OCTGT Office Update

  • Donor Testing

  • Inspections

  • Regulatory Actions

  • Deviation Reports

  • Adverse Reaction Data

  • Follow-Up on Legal Issues


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OCTGT Update

  • Three new research programs

    • Retroviral vectors

    • Tissue safety

      • Shyh-Ching Lo

      • Joydeep Ghosh

    • Tolerance and immune regulation


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A new Tissue Laboratory developed under the Division of Cellular & Gene Therapies (DCGT) in collaboration with the Division of Human Tissues (DHT) of OCTGT/CBER/FDA:

  • Promote safety of tissue grafts for transplantation

    • Understand and help validation of various procedures for human tissue processing

    • Support evaluation of licensed donor screening tests

    • Develop and apply new methodologies for detection of microbes in tissues to be used as grafts

    • Develop capability of identification and characterization of microbes associated with unusual infections or emerging infectious diseases

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


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

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

Evaluation and application of high-throughput sequencing technology for identification of unusual microbes 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.

Tissue lab capabilities to be developed:


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Guidances in Development characterization of various microbes with tissue safety concerns

  • Characterization and Qualification of Cell Banks Used in the Production of Cellular and Gene Therapy Products

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

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


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Guidances in Development characterization of various microbes with tissue safety concerns

  • Preparation of INDs for Certain Unlicensed Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Products (HPC-C)

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

  • Clinical Study Design Considerations for Cancer Vaccine Development

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


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Guidances in Development characterization of various microbes with tissue safety concerns

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

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

  • Submission of Information for the National Xenotransplantation Database


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Regulation characterization of various microbes with tissue safety concerns

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


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Guidance characterization of various microbes with tissue safety concerns

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

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


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Guidance characterization of various microbes with tissue safety concerns

  • Draft Guidance for Industry: Use of Nucleic Acid Tests to Reduce the Risk of Transmission of West Nile Virus from Donors of Whole Blood and Blood Components Intended for Transfusion and Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) 4/25/08

    • Two FDA-licensed tests for living and cadaveric donors

    • All HCT/P donors tested by Individual Donor NAT

    • Comments under review

  • Request for Data 7/7/2008

    • Request for complete data for 2008 WNV season by 1/31/09


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Guidance characterization of various microbes with tissue safety concerns

  • Guidance for Industry: CGMP for Phase 1 Investigational Drugs 7/15/2008

    • Well-defined written procedures

    • Adequately controlled equipment and manufacturing environment

    • Accurately and consistently recorded data from manufacturing (including testing)

  • Draft Guidance for Industry: Considerations for Allogeneic Pancreatic Islet Cell Products 5/21/2008


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Guidance characterization of various microbes with tissue safety concerns

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

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


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Guidance characterization of various microbes with tissue safety concerns

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


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Guidance characterization of various microbes with tissue safety concerns

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


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Guidance characterization of various microbes with tissue safety concerns

  • Draft Chagas guidance, cont.

    • Not for implementation

    • Notification of intent to make Chagas Disease (T. cruzi infection) a RCDAD

    • Makes recommendations for donor screening and testing

    • Docket open for comments


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Regulations/Guidance characterization of various microbes with tissue safety concerns

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

  • http://www.fda.gov/cber/rules.htm


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Meetings/Workshops characterization of various microbes with tissue safety concerns

  • Animal Models for the Treatment of Acute Radiation Syndrome September 17-18, 2008

  • Public Workshop: America’s Blood Centers: Blood Establishment Computer Software (BECS) Conference July 10-11, 2008

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


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Meetings/Workshops characterization of various microbes with tissue safety concerns

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

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


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Meetings/Workshops characterization of various microbes with tissue safety concerns

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

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


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HCT/P Donor Tests for RCDADs characterization of various microbes with tissue safety concerns

  • Updated listing of all available donor screening tests and appropriate specimens (originally posted Feb 2007) at: http://www.fda.gov/cber/tissue/prod.

    htm#approved

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


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HRSA RFI on Vascularized Composite Allografts characterization of various microbes with tissue safety concerns

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

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

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

  • Comment period closed May 2, 2008

  • Contact HRSA for more info:

    301-443-7577


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General Testing Requirements characterization of various microbes with tissue safety concerns

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


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

  • HCV NAT:

    • COBAS Ampliscreen HCV Test, version 2.0: Living donor (LD) specimens, maximum time frozen is one month; cadaveric specimens (CAD) up to 72 hours.

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

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

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


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

  • HIV NAT: same as for HCV NAT

    • COBAS Ampliscreen HIV-1 Test has same storage claim as the Ampliscreen HCV test – up to one month

    • all other tests are the same


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Antibody Test Storage Claims screening tests

  • Many have language similar to below*:

    For cadaveric specimens, follow general standards and/or regulations for collection, storage and handling. Cadaveric specimens may be stored frozen (-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 anticipated, the serum should be removed from the clot to avoid hemolysis and stored frozen.

    * Abbott PRISM HBsAg Assay


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Antibody Test Storage Claims screening tests

Ortho HCV and Chagas ELISA tests (Ab)

  • Cadaveric specimens may be stored for up to 10 days at 2-8°C and up to 4 weeks at –20°C undergoing 5 freeze/thaw cycles. Store specimens in appropriately qualified freezers. Specimens may be frozen and thawed up to 5 times. Mix specimen thoroughly after thawing and before testing.

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


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FY08 HCT/P screening testsInspections Accomplished

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


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FY08 HCT/P screening testsInspection Classifications


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FDA Form 483 screening tests

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


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OAI/VAI/NAI? screening tests

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

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

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

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


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FY08 HCT/P screening testsInspection Results

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

  • Consistent with FY07 and FY06.


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Inspectional Observations: screening testsStorage and Distribution

  • Failure to store HCT/Ps at appropriate temperatures; establish acceptable temperature limits; and/or maintain and record storage temperatures 21 CFR 1271.260 (b) and (e)

    • Storage room temperatures are not recorded

    • Freezer did not have a functioning recording device and was not equipped with an alarm. The freezer temperature is not recorded or monitored after normal operating hours

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


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Inspectional Observations: screening testsProcessors

  • Failure to maintain facility in good state of repair 21 CFR 1271.190(a)

    • Several processing rooms have damage to the walls – areas of damage show exposed dry wall below the level of the paper layer

  • Failure to maintain documentation of equipment maintenance, cleaning, sanitization and calibration 21 CFR 1271. 200(e)

    • Cleaning of equipment was not documented. There were no records of cleaning from 1/2006 – 3/2008


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Inspectional Observations: screening testsProcessors - 2

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

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


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Inspectional Observations: screening testsDonor Testing

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

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


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Regulatory Actions screening tests

  • Regulatory Actions Issued

    • 1 Warning Letter (repro)

    • 1 Untitled Letter (repro)

    • 1 Untitled Letter –website/stem cell treatment – part of our internet surveillance


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FY08 HCT/P Regulatory Actions: Deviations Cited screening tests

  • Failure to test specimens from anonymous or directed reproductive donors using appropriate FDA-licensed, approved, or cleared donor screening tests, in accordance with the manufacturer's instructions21 CFR 1271.80(c).

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


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Regulatory Actions - 2 screening tests

  • 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.


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HCT/P Deviation Reporting screening tests


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HCT/P Deviation Reports screening testsProducts Involved


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HCT/P Deviations Reported screening tests


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HCT/P Deviation Reports screening testsNon-Reportable Events

  • No products were distributed

  • Not associated with disease transmission or contamination

  • Not related to core GTP

  • Product released under urgent medical need

  • Product not subject to HCT/P deviation reporting

    • Reproductive tissue

    • Unrelated Allogeneic Stem Cells

  • Reporting establishment is not an HCT/P manufacturer


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HCT/P Deviation Reports screening testsNon-Reportable Events

  • Positive pre-implant culture is in general not reportable as a deviation

    • Unless a complaint results in an investigation that reveals a departure from GTPs or

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



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Tissue HCT/P Reports screening tests

  • Donor Eligibility – 33 reports

    • Donor accepted when risk factors, clinical evidence or physical evidence identified – 18

    • Donor accepted when reactive for relevant communicable disease – 4

    • Donor incorrectly evaluated for plasma dilution – 10

    • Donor testing not performed or documented - 1


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Tissue HCT/P Reports - 2 screening tests

  • Processing and process controls – 18

    • HCT/P contaminated, potentially contaminated or cross contaminated – 17

    • In-process controls inadequate – 1

  • Microorganisms involved:

    • Bacillus, Candida, Clostridium, Enterobacter, Group D Enterococcus, Staphylococcus, Proteus


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Tissue HCT/P Reports - 3 screening tests

  • Donor Screening – 15

    • Donor screening not performed or documented – 1

    • Donor screening (medical history interview) performed incorrectly (incomplete or inaccurate) – 13

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


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Classified Recalls screening testsFY 2007


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Classified Recalls screening testsFY 2008*

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


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FY 2008 Class I screening testsHCT/P Recalls

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

    • 2 recalls

  • Clostridium perfringens infection in recipient.


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HCT/P Recalls screening tests


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Adverse Reaction Data screening tests


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Adverse Reactions Reported screening tests* by Tissue Type

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

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


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Reported Adverse Reactions by Outcome screening tests

* Data for 2005 includes only reports after May 25

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


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Reported Adverse Reactions by Reported Organism screening tests

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


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Biomedical Tissue Services (BTS) screening testsOrder to Cease and Retain HCT/Ps

  • Immediately cease manufacturing operations and retain HCT/Ps.

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

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

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

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


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BTS Order screening tests

  • Despite records maintaining otherwise:

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

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

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

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


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CDC: MMWR screening testsBrief Report May 26, 2006

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

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

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

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


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MMWR cont.. screening tests

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


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BTS Update screening tests

  • In March 2008, Michael Mastromarino pleaded guilty in Brooklyn Supreme Court to body stealing, forgery, grand larceny and enterprise corruption and was sentenced to 18 to 54 years. He is serving a concurrent sentence of 25 to 58 years after pleading guilty to similar changes in Philadelphia.

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

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


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BTS Update - 2 screening tests

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

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

  • Six others are expected to stand trial in Rochester

  • FDA will continue to work cooperatively with other Federal, State and local authorities


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

  • Immediately cease manufacturing operations and retain HCT/Ps.

  • To DRS and its Owner, Philip Guyett

  • FDA determined that the violations uncovered at DRS, because of their serious nature, constitute a danger to health and took action

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

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


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DRS Order and Retain HCT/Ps

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

    • Cause, place, and time of death


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DRS Public Health Notification and Retain HCT/Ps

  • August 30, 2006

  • FDA and CDC strongly recommended health care providers inform all patients that received tissue initially recovered by DRS and offer access to communicable disease testing

  • Distributing firms had already voluntarily recalled tissue in inventory

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


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DRS Update and Retain HCT/Ps

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

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

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


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CBER Information and Retain HCT/Ps


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